US8541596B2 - Inhibitors - Google Patents
Inhibitors Download PDFInfo
- Publication number
- US8541596B2 US8541596B2 US13/091,276 US201113091276A US8541596B2 US 8541596 B2 US8541596 B2 US 8541596B2 US 201113091276 A US201113091276 A US 201113091276A US 8541596 B2 US8541596 B2 US 8541596B2
- Authority
- US
- United States
- Prior art keywords
- benzo
- amine
- imidazol
- alkyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 **NC(C(CCCC(N)=O)N)=O Chemical compound **NC(C(CCCC(N)=O)N)=O 0.000 description 22
- MHYFPGNKSIMVQE-UHFFFAOYSA-N CC(C)(C)C1=CC=C(CN(CC2=CC=C(C(C)(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CC(C)(C)C1=CC=C(CN(CC2=CC=C(C(C)(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 MHYFPGNKSIMVQE-UHFFFAOYSA-N 0.000 description 4
- CHJNDNFGIHVRPJ-UHFFFAOYSA-N CCC1=CC=C(CN(C/C2=N/C3=C(C=CC=C3)S2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CCC1=CC=C(CN(C/C2=N/C3=C(C=CC=C3)S2)C2=CC3=C(C=C2)NC=N3)C=C1 CHJNDNFGIHVRPJ-UHFFFAOYSA-N 0.000 description 4
- NXMIJURLBSNANE-UHFFFAOYSA-N C1=CSC(C2=CC=C(CN(CC3=CC=C(C4=CC=CS4)C=C3)C3=CC4=C(C=C3)NC=N4)C=C2)=C1 Chemical compound C1=CSC(C2=CC=C(CN(CC3=CC=C(C4=CC=CS4)C=C3)C3=CC4=C(C=C3)NC=N4)C=C2)=C1 NXMIJURLBSNANE-UHFFFAOYSA-N 0.000 description 3
- FZXIQDGQTINREM-UHFFFAOYSA-N CC1=CC=C(CN(CC2=CC=C(C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CC1=CC=C(CN(CC2=CC=C(C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 FZXIQDGQTINREM-UHFFFAOYSA-N 0.000 description 3
- OQNQMPVEUGQMHY-UHFFFAOYSA-N CCC1=CC=C(CN(CC2=CC(F)=C(F)C(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CCC1=CC=C(CN(CC2=CC(F)=C(F)C(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 OQNQMPVEUGQMHY-UHFFFAOYSA-N 0.000 description 3
- HRBMQFIQKYWSTO-UHFFFAOYSA-N COC1=CC=C(CN(CC2=CC=C(N(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound COC1=CC=C(CN(CC2=CC=C(N(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 HRBMQFIQKYWSTO-UHFFFAOYSA-N 0.000 description 3
- GPSDSRNWDNFRLE-UHFFFAOYSA-N COC1=CC=CC(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)=C1 Chemical compound COC1=CC=CC(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)=C1 GPSDSRNWDNFRLE-UHFFFAOYSA-N 0.000 description 3
- LZRRMVYWOREWNL-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=C(Cl)C=CC(Cl)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=C(Cl)C=CC(Cl)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 LZRRMVYWOREWNL-UHFFFAOYSA-N 0.000 description 3
- WFRXSXUDWCVSPI-UHFFFAOYSA-N Nc(cc1)cc2c1[nH]cn2 Chemical compound Nc(cc1)cc2c1[nH]cn2 WFRXSXUDWCVSPI-UHFFFAOYSA-N 0.000 description 3
- LPYGGACUIUCXPW-UHFFFAOYSA-N BrC1=CC=C(CN(CC2=CC=C(Br)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound BrC1=CC=C(CN(CC2=CC=C(Br)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 LPYGGACUIUCXPW-UHFFFAOYSA-N 0.000 description 2
- PKVPNEGDNXQLLT-UHFFFAOYSA-N BrC1=CC=CC(CN(CC2=CC(Br)=CC=C2)C2=CC3=C(C=C2)NC=N3)=C1 Chemical compound BrC1=CC=CC(CN(CC2=CC(Br)=CC=C2)C2=CC3=C(C=C2)NC=N3)=C1 PKVPNEGDNXQLLT-UHFFFAOYSA-N 0.000 description 2
- OGSLPXATSMVZSQ-UHFFFAOYSA-N C1=CC2=C(C=C1)S/C(CN(C/C1=N/C3=C(C=CC=C3)S1)C1=CC3=C(C=C1)NC=N3)=N\2 Chemical compound C1=CC2=C(C=C1)S/C(CN(C/C1=N/C3=C(C=CC=C3)S1)C1=CC3=C(C=C1)NC=N3)=N\2 OGSLPXATSMVZSQ-UHFFFAOYSA-N 0.000 description 2
- ZOJZYJYVVABUTE-UHFFFAOYSA-N C1=CC2=CC=C(CN(CC3=CC4=C(C=CC=C4)C=C3)C3=CC4=C(C=C3)NC=N4)C=C2C=C1 Chemical compound C1=CC2=CC=C(CN(CC3=CC4=C(C=CC=C4)C=C3)C3=CC4=C(C=C3)NC=N4)C=C2C=C1 ZOJZYJYVVABUTE-UHFFFAOYSA-N 0.000 description 2
- RYHKMGMMYIHEBG-UHFFFAOYSA-N C1=CC2=NSN=C2C=C1CN(CC1=CC2=NSN=C2C=C1)C1=CC2=C(C=C1)NC=N2 Chemical compound C1=CC2=NSN=C2C=C1CN(CC1=CC2=NSN=C2C=C1)C1=CC2=C(C=C1)NC=N2 RYHKMGMMYIHEBG-UHFFFAOYSA-N 0.000 description 2
- PRDYHJHPNNEEPO-UHFFFAOYSA-N C1=CC=C(CCC2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound C1=CC=C(CCC2=CC3=C(C=C2)NC=N3)C=C1 PRDYHJHPNNEEPO-UHFFFAOYSA-N 0.000 description 2
- CJWCLTZTYFVKTN-UHFFFAOYSA-N C1=CC=C(CN(C2=CC=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound C1=CC=C(CN(C2=CC=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 CJWCLTZTYFVKTN-UHFFFAOYSA-N 0.000 description 2
- ODTDPOHJQLKVOL-UHFFFAOYSA-N C1=CC=C(CN(CC2=CC=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound C1=CC=C(CN(CC2=CC=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 ODTDPOHJQLKVOL-UHFFFAOYSA-N 0.000 description 2
- QBYAGUCJTFDQGE-UHFFFAOYSA-N CC(C)C1=CC=C(CN(CC2=CC=C(C(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CC(C)C1=CC=C(CN(CC2=CC=C(C(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 QBYAGUCJTFDQGE-UHFFFAOYSA-N 0.000 description 2
- ZSJJEIXMCUMMNG-UHFFFAOYSA-N CC.[H]N([H])C1=CC2=C(C=C1)N([H])C=N2 Chemical compound CC.[H]N([H])C1=CC2=C(C=C1)N([H])C=N2 ZSJJEIXMCUMMNG-UHFFFAOYSA-N 0.000 description 2
- LFHIDSBOZLLARM-UHFFFAOYSA-N CC1=CC=C(CN(CC2=CC=C(N(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CC1=CC=C(CN(CC2=CC=C(N(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 LFHIDSBOZLLARM-UHFFFAOYSA-N 0.000 description 2
- AQCJAYRJGSXTSA-UHFFFAOYSA-N CC1=CC=CC(CN(CC2=C(F)C(C)=CC=C2)C2=CC3=C(C=C2)NC=N3)=C1F Chemical compound CC1=CC=CC(CN(CC2=C(F)C(C)=CC=C2)C2=CC3=C(C=C2)NC=N3)=C1F AQCJAYRJGSXTSA-UHFFFAOYSA-N 0.000 description 2
- VWWMGPCUZVOLLK-UHFFFAOYSA-N CC1=CC=NC2=C1N=C(C1CC1)N2CC1=CC=C(C2=C(C(=O)O)C=CC=C2)C=C1 Chemical compound CC1=CC=NC2=C1N=C(C1CC1)N2CC1=CC=C(C2=C(C(=O)O)C=CC=C2)C=C1 VWWMGPCUZVOLLK-UHFFFAOYSA-N 0.000 description 2
- XENDATVUHZYPQP-UHFFFAOYSA-N CC1=NC2=CC=C(CN(CC3=CC4=C(C=C3)N=C(C)C=C4)C3=CC4=C(C=C3)NC=N4)C=C2C=C1 Chemical compound CC1=NC2=CC=C(CN(CC3=CC4=C(C=C3)N=C(C)C=C4)C3=CC4=C(C=C3)NC=N4)C=C2C=C1 XENDATVUHZYPQP-UHFFFAOYSA-N 0.000 description 2
- YHBCLKVYMVAEFE-UHFFFAOYSA-N CCC1=CC=C(CN(CC2=C(F)C(F)=C(C)C(F)=C2F)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CCC1=CC=C(CN(CC2=C(F)C(F)=C(C)C(F)=C2F)C2=CC3=C(C=C2)NC=N3)C=C1 YHBCLKVYMVAEFE-UHFFFAOYSA-N 0.000 description 2
- JDBZWVGFYBDNPO-UHFFFAOYSA-N CCC1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CCC1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 JDBZWVGFYBDNPO-UHFFFAOYSA-N 0.000 description 2
- PPQHHHGGBXZOIH-UHFFFAOYSA-N CCC1=CC=C(CN(CC2=CC=C(C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CCC1=CC=C(CN(CC2=CC=C(C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 PPQHHHGGBXZOIH-UHFFFAOYSA-N 0.000 description 2
- KDAOIKMTRVZUAU-UHFFFAOYSA-N CCC1=CC=C(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CCC1=CC=C(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 KDAOIKMTRVZUAU-UHFFFAOYSA-N 0.000 description 2
- AXAMCBRYWQVKIY-UHFFFAOYSA-N CCC1=CC=C(CN(CC2=CSC3=C2C=C(Cl)C=C3)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CCC1=CC=C(CN(CC2=CSC3=C2C=C(Cl)C=C3)C2=CC3=C(C=C2)NC=N3)C=C1 AXAMCBRYWQVKIY-UHFFFAOYSA-N 0.000 description 2
- KDPZQBMDLGPABQ-UHFFFAOYSA-N CN(C)C1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CN(C)C1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 KDPZQBMDLGPABQ-UHFFFAOYSA-N 0.000 description 2
- YCSHVGKLFMRYRX-UHFFFAOYSA-N COC1=CC(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)=CC(OC)=C1 Chemical compound COC1=CC(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)=CC(OC)=C1 YCSHVGKLFMRYRX-UHFFFAOYSA-N 0.000 description 2
- JMXDDDQZGVUFAW-UHFFFAOYSA-N COC1=CC(F)=C(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1OC Chemical compound COC1=CC(F)=C(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1OC JMXDDDQZGVUFAW-UHFFFAOYSA-N 0.000 description 2
- CKCLHHOPAZYGRH-UHFFFAOYSA-N COC1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound COC1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 CKCLHHOPAZYGRH-UHFFFAOYSA-N 0.000 description 2
- WEPOFFXOZZPKJT-UHFFFAOYSA-N COC1=CC=C(CN(CC2=CC=C(OC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound COC1=CC=C(CN(CC2=CC=C(OC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 WEPOFFXOZZPKJT-UHFFFAOYSA-N 0.000 description 2
- QHZPJEXPSRYMHO-UHFFFAOYSA-N COC1=CC=C(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound COC1=CC=C(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 QHZPJEXPSRYMHO-UHFFFAOYSA-N 0.000 description 2
- WMMOZGWFVPDRPW-UHFFFAOYSA-N COC1=CC=C(CN(CC2=CC=CC=C2)C2=CC3=C(C=C2)N=CC3)C=C1 Chemical compound COC1=CC=C(CN(CC2=CC=CC=C2)C2=CC3=C(C=C2)N=CC3)C=C1 WMMOZGWFVPDRPW-UHFFFAOYSA-N 0.000 description 2
- XQGXEZBEODTOAQ-UHFFFAOYSA-N COC1=CC=C(CN(CCC2=CC=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound COC1=CC=C(CN(CCC2=CC=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 XQGXEZBEODTOAQ-UHFFFAOYSA-N 0.000 description 2
- HVYYOHKMUKCOOS-UHFFFAOYSA-N COC1=CC=CC(CN(CC2=CC(OC)=CC=C2)C2=CC3=C(C=C2)NC=N3)=C1 Chemical compound COC1=CC=CC(CN(CC2=CC(OC)=CC=C2)C2=CC3=C(C=C2)NC=N3)=C1 HVYYOHKMUKCOOS-UHFFFAOYSA-N 0.000 description 2
- YCENJSXPKANNNX-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=C(F)C(C)=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=C(F)C(C)=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 YCENJSXPKANNNX-UHFFFAOYSA-N 0.000 description 2
- PIAMIZQMERRHRH-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=C(F)C(F)=C(C)C(F)=C2F)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=C(F)C(F)=C(C)C(F)=C2F)C2=CC3=C(C=C2)NC=N3)C=C1 PIAMIZQMERRHRH-UHFFFAOYSA-N 0.000 description 2
- GHBBKJODXCHMLY-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=C(F)C=C(F)C(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=C(F)C=C(F)C(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 GHBBKJODXCHMLY-UHFFFAOYSA-N 0.000 description 2
- MMRDSEGONWYPBC-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CC(F)=C(F)C(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CC(F)=C(F)C(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 MMRDSEGONWYPBC-UHFFFAOYSA-N 0.000 description 2
- YPSXEXKDJAOHFA-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CC(F)=CC(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CC(F)=CC(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1 YPSXEXKDJAOHFA-UHFFFAOYSA-N 0.000 description 2
- PLEIYXJZFUZQKZ-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 PLEIYXJZFUZQKZ-UHFFFAOYSA-N 0.000 description 2
- IWMZKEUELITHDH-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CC=C(Br)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CC=C(Br)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 IWMZKEUELITHDH-UHFFFAOYSA-N 0.000 description 2
- PSIXDYWHIJXZHD-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CC=C(C(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CC=C(C(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 PSIXDYWHIJXZHD-UHFFFAOYSA-N 0.000 description 2
- YDLXZKRNUMZZGW-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CC=C(C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CC=C(C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 YDLXZKRNUMZZGW-UHFFFAOYSA-N 0.000 description 2
- VHONMFGGVFEECM-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CC=C(N(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CC=C(N(C)C)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 VHONMFGGVFEECM-UHFFFAOYSA-N 0.000 description 2
- ITXFHTAEQJDQMZ-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CC=C(SC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 ITXFHTAEQJDQMZ-UHFFFAOYSA-N 0.000 description 2
- FXQVCBPFDPNMIH-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CC=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CC=CC=C2)C2=CC3=C(C=C2)NC=N3)C=C1 FXQVCBPFDPNMIH-UHFFFAOYSA-N 0.000 description 2
- VNDKYUKRPJQKET-UHFFFAOYSA-N CSC1=CC=C(CN(CC2=CSC3=C2C=C(Cl)C=C3)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2=CSC3=C2C=C(Cl)C=C3)C2=CC3=C(C=C2)NC=N3)C=C1 VNDKYUKRPJQKET-UHFFFAOYSA-N 0.000 description 2
- CETFWDFWYCNWEQ-UHFFFAOYSA-N CSC1=CC=C(CN(CC2CCCCC2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC2CCCCC2)C2=CC3=C(C=C2)NC=N3)C=C1 CETFWDFWYCNWEQ-UHFFFAOYSA-N 0.000 description 2
- WAUMYUUODLQZBK-UHFFFAOYSA-N ClC1=CC2=C(C=C1)SC=C2CN(CC1=CSC2=C1C=C(Cl)C=C2)C1=CC2=C(C=C1)NC=N2 Chemical compound ClC1=CC2=C(C=C1)SC=C2CN(CC1=CSC2=C1C=C(Cl)C=C2)C1=CC2=C(C=C1)NC=N2 WAUMYUUODLQZBK-UHFFFAOYSA-N 0.000 description 2
- AGCIQZYITOBLBR-UHFFFAOYSA-N ClC1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound ClC1=CC=C(CN(CC2=CC3=NSN=C3C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 AGCIQZYITOBLBR-UHFFFAOYSA-N 0.000 description 2
- WDYZZVRJDHBIBK-UHFFFAOYSA-N FC1=C(CN(CC2=C(F)C=CC=C2)C2=CC3=C(C=C2)NC=N3)C=CC=C1 Chemical compound FC1=C(CN(CC2=C(F)C=CC=C2)C2=CC3=C(C=C2)NC=N3)C=CC=C1 WDYZZVRJDHBIBK-UHFFFAOYSA-N 0.000 description 2
- ZFUAIBFOROMRJC-UHFFFAOYSA-N FC1=CC(F)=C(CN(CC2=C(F)C=C(F)C(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1F Chemical compound FC1=CC(F)=C(CN(CC2=C(F)C=C(F)C(F)=C2)C2=CC3=C(C=C2)NC=N3)C=C1F ZFUAIBFOROMRJC-UHFFFAOYSA-N 0.000 description 2
- KTTHZLPKNPJIOV-UHFFFAOYSA-N FC1=CC(F)=CC(CN(CC2=CC(F)=CC(F)=C2)C2=CC3=C(C=C2)NC=N3)=C1 Chemical compound FC1=CC(F)=CC(CN(CC2=CC(F)=CC(F)=C2)C2=CC3=C(C=C2)NC=N3)=C1 KTTHZLPKNPJIOV-UHFFFAOYSA-N 0.000 description 2
- BJCMCXNGDKLQOB-UHFFFAOYSA-N N#CC1=CC=C(CN(CC2=CC=C(C#N)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound N#CC1=CC=C(CN(CC2=CC=C(C#N)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 BJCMCXNGDKLQOB-UHFFFAOYSA-N 0.000 description 2
- IKEKXKXTFVBGSA-UHFFFAOYSA-N [C-]#[N+]C1=CC=C(CN(CC2=CC=C(CC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound [C-]#[N+]C1=CC=C(CN(CC2=CC=C(CC)C=C2)C2=CC3=C(C=C2)NC=N3)C=C1 IKEKXKXTFVBGSA-UHFFFAOYSA-N 0.000 description 2
- SYRBMEKFEDRNDB-UHFFFAOYSA-N BrC1=CC=CC(CCC2=CC3=C(C=C2)NC=N3)=C1 Chemical compound BrC1=CC=CC(CCC2=CC3=C(C=C2)NC=N3)=C1 SYRBMEKFEDRNDB-UHFFFAOYSA-N 0.000 description 1
- MDIXJDARVZRQNB-UHFFFAOYSA-N Brc1cc(CNc(cc2)cc3c2[nH]cn3)ccc1 Chemical compound Brc1cc(CNc(cc2)cc3c2[nH]cn3)ccc1 MDIXJDARVZRQNB-UHFFFAOYSA-N 0.000 description 1
- ZJLQREMBJCZYRA-UHFFFAOYSA-N C(c1cc2n[s]nc2cc1)Nc(cc1)cc2c1[nH]cn2 Chemical compound C(c1cc2n[s]nc2cc1)Nc(cc1)cc2c1[nH]cn2 ZJLQREMBJCZYRA-UHFFFAOYSA-N 0.000 description 1
- FSRYAPDLWNOBIU-UHFFFAOYSA-N C(c1ccccc1)Nc(cc1)cc2c1[nH]cn2 Chemical compound C(c1ccccc1)Nc(cc1)cc2c1[nH]cn2 FSRYAPDLWNOBIU-UHFFFAOYSA-N 0.000 description 1
- KUEFKTLZEFJCLM-WTDSWWLTSA-N C/C=N/C1=CC2=C(C=C1)NC=N2 Chemical compound C/C=N/C1=CC2=C(C=C1)NC=N2 KUEFKTLZEFJCLM-WTDSWWLTSA-N 0.000 description 1
- XOHPGSFHBBCJKS-UHFFFAOYSA-N C1=CC(CCC2=CC3=C(C=C2)NC=N3)=C2OCCCOC2=C1 Chemical compound C1=CC(CCC2=CC3=C(C=C2)NC=N3)=C2OCCCOC2=C1 XOHPGSFHBBCJKS-UHFFFAOYSA-N 0.000 description 1
- HXIPJWQLHLVRIT-UHFFFAOYSA-N C1=CC(CN(CC2=C3OCCCOC3=CC=C2)C2=CC3=C(C=C2)NC=N3)=C2OCCCOC2=C1 Chemical compound C1=CC(CN(CC2=C3OCCCOC3=CC=C2)C2=CC3=C(C=C2)NC=N3)=C2OCCCOC2=C1 HXIPJWQLHLVRIT-UHFFFAOYSA-N 0.000 description 1
- ITBDXDJMVJMPSW-UHFFFAOYSA-N C1=CC2=C(C=C1)C=C(CCC1=CC3=C(C=C1)NC=N3)C=C2 Chemical compound C1=CC2=C(C=C1)C=C(CCC1=CC3=C(C=C1)NC=N3)C=C2 ITBDXDJMVJMPSW-UHFFFAOYSA-N 0.000 description 1
- IPMCEMKCUPQQNP-UHFFFAOYSA-N C1=CC2=C(C=C1)S/C(CCC1=CC3=C(C=C1)NC=N3)=N\2 Chemical compound C1=CC2=C(C=C1)S/C(CCC1=CC3=C(C=C1)NC=N3)=N\2 IPMCEMKCUPQQNP-UHFFFAOYSA-N 0.000 description 1
- VPPCKBGGJKVVJW-UHFFFAOYSA-N C1=CC2=C(C=C1CCC1CCCCC1)N=CN2 Chemical compound C1=CC2=C(C=C1CCC1CCCCC1)N=CN2 VPPCKBGGJKVVJW-UHFFFAOYSA-N 0.000 description 1
- FFXYXWGRKIGCSC-UHFFFAOYSA-N C1=CC2=NSN=C2C=C1CCC1=CC2=C(C=C1)NC=N2 Chemical compound C1=CC2=NSN=C2C=C1CCC1=CC2=C(C=C1)NC=N2 FFXYXWGRKIGCSC-UHFFFAOYSA-N 0.000 description 1
- UNMRFJRNKSLHOM-UHFFFAOYSA-N C1=CC=C(CC2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound C1=CC=C(CC2=CC3=C(C=C2)NC=N3)C=C1 UNMRFJRNKSLHOM-UHFFFAOYSA-N 0.000 description 1
- UBZHWPNVAZRUTC-UHFFFAOYSA-N C1=CC=C(CCCC2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound C1=CC=C(CCCC2=CC3=C(C=C2)NC=N3)C=C1 UBZHWPNVAZRUTC-UHFFFAOYSA-N 0.000 description 1
- OUDNSGNNBNQSTL-UHFFFAOYSA-N C1=CC=C(CCCCC2=CC=C3NC=NC3=C2)C=C1 Chemical compound C1=CC=C(CCCCC2=CC=C3NC=NC3=C2)C=C1 OUDNSGNNBNQSTL-UHFFFAOYSA-N 0.000 description 1
- ZQTNQZBVLMMYPC-UHFFFAOYSA-N C1=CSC(C2=CC=C(CCC3=CC4=C(C=C3)NC=N4)C=C2)=C1 Chemical compound C1=CSC(C2=CC=C(CCC3=CC4=C(C=C3)NC=N4)C=C2)=C1 ZQTNQZBVLMMYPC-UHFFFAOYSA-N 0.000 description 1
- NYUPPOCIQRGVKL-UHFFFAOYSA-N CC(C)CCC1=CC2=C(C=C1)NC=N2 Chemical compound CC(C)CCC1=CC2=C(C=C1)NC=N2 NYUPPOCIQRGVKL-UHFFFAOYSA-N 0.000 description 1
- ITZZJJGXKYCXRR-UHFFFAOYSA-N CC(CC1=CC2=C(C=C1)N=CC2)C1=CC=CC=C1 Chemical compound CC(CC1=CC2=C(C=C1)N=CC2)C1=CC=CC=C1 ITZZJJGXKYCXRR-UHFFFAOYSA-N 0.000 description 1
- DKXWMISXMXRPMR-UHFFFAOYSA-N CC(c1ccccc1)Nc(cc1)cc2c1nc[nH]2 Chemical compound CC(c1ccccc1)Nc(cc1)cc2c1nc[nH]2 DKXWMISXMXRPMR-UHFFFAOYSA-N 0.000 description 1
- AUBFXSIUWRJKQO-UHFFFAOYSA-N CC.[H]C(=O)CC1=CC2=C(C=C1)N([H])C=N2 Chemical compound CC.[H]C(=O)CC1=CC2=C(C=C1)N([H])C=N2 AUBFXSIUWRJKQO-UHFFFAOYSA-N 0.000 description 1
- AFORSUAXJIWYCX-JVSGEUHRSA-N CC.[H]N1C=NC2=C1C=CC(/N=C/C)=C2 Chemical compound CC.[H]N1C=NC2=C1C=CC(/N=C/C)=C2 AFORSUAXJIWYCX-JVSGEUHRSA-N 0.000 description 1
- YBIWVDQOXRRURR-UHFFFAOYSA-N CC.[H]N1C=NC2=C1C=CC(C)=C2 Chemical compound CC.[H]N1C=NC2=C1C=CC(C)=C2 YBIWVDQOXRRURR-UHFFFAOYSA-N 0.000 description 1
- JYHJJGBYNLHZAK-UHFFFAOYSA-N CC1=C(F)C(F)=C(CCC2=CC3=C(C=C2)NC=N3)C(F)=C1F Chemical compound CC1=C(F)C(F)=C(CCC2=CC3=C(C=C2)NC=N3)C(F)=C1F JYHJJGBYNLHZAK-UHFFFAOYSA-N 0.000 description 1
- RWXZXCZBMQPOBF-UHFFFAOYSA-N CC1=CC2=C(C=C1)NC=N2 Chemical compound CC1=CC2=C(C=C1)NC=N2 RWXZXCZBMQPOBF-UHFFFAOYSA-N 0.000 description 1
- MVOBVLTZSFLVTP-UHFFFAOYSA-N CC1=CC=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 Chemical compound CC1=CC=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 MVOBVLTZSFLVTP-UHFFFAOYSA-N 0.000 description 1
- RAUPSEKUADWROT-UHFFFAOYSA-N CC1=CC=CC(CCC2=CC3=C(C=C2)NC=N3)=C1F Chemical compound CC1=CC=CC(CCC2=CC3=C(C=C2)NC=N3)=C1F RAUPSEKUADWROT-UHFFFAOYSA-N 0.000 description 1
- JFYQTKZWAUIXBP-UHFFFAOYSA-N CC1=NC2=C(C=C1)C=C(CCC1=CC3=C(C=C1)NC=N3)C=C2 Chemical compound CC1=NC2=C(C=C1)C=C(CCC1=CC3=C(C=C1)NC=N3)C=C2 JFYQTKZWAUIXBP-UHFFFAOYSA-N 0.000 description 1
- POOKIWDXVJAZBR-UHFFFAOYSA-N CCC(C)(C)CC.CCC(C)C(C)C.CCC(C)C(C)C.CCC(C)CC Chemical compound CCC(C)(C)CC.CCC(C)C(C)C.CCC(C)C(C)C.CCC(C)CC POOKIWDXVJAZBR-UHFFFAOYSA-N 0.000 description 1
- PBJADZQATFYIHD-UHFFFAOYSA-N CCC1=CC=C(CCC2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CCC1=CC=C(CCC2=CC3=C(C=C2)NC=N3)C=C1 PBJADZQATFYIHD-UHFFFAOYSA-N 0.000 description 1
- MSMRCIHTUVQMEX-UHFFFAOYSA-N CCC1=NC2=C(C=CC=C2)C(OCC2=CC=C(C3=C(C4=NN=NN4)C=CC=C3)C=C2)=C1.[H]C Chemical compound CCC1=NC2=C(C=CC=C2)C(OCC2=CC=C(C3=C(C4=NN=NN4)C=CC=C3)C=C2)=C1.[H]C MSMRCIHTUVQMEX-UHFFFAOYSA-N 0.000 description 1
- ZPHMLHZDMTUNKD-UHFFFAOYSA-N CCCC(C)CC1=CC2=C(C=C1)NC=N2 Chemical compound CCCC(C)CC1=CC2=C(C=C1)NC=N2 ZPHMLHZDMTUNKD-UHFFFAOYSA-N 0.000 description 1
- KEPHAERSIOJRIT-UHFFFAOYSA-N CCCC(C)N(CC1=CC=C(SC)C=C1)C1=CC2=C(C=C1)NC=N2 Chemical compound CCCC(C)N(CC1=CC=C(SC)C=C1)C1=CC2=C(C=C1)NC=N2 KEPHAERSIOJRIT-UHFFFAOYSA-N 0.000 description 1
- UZJNZLJCJGLFKK-UHFFFAOYSA-N CCCCC1=NN(CC2=CN=C(C3=C(C4=NN=NN4)C=CC=C3)C=C2)C(CCCC)=N1.[H]C Chemical compound CCCCC1=NN(CC2=CN=C(C3=C(C4=NN=NN4)C=CC=C3)C=C2)C(CCCC)=N1.[H]C UZJNZLJCJGLFKK-UHFFFAOYSA-N 0.000 description 1
- TVMPLXPPESHIEQ-UHFFFAOYSA-N CCCCCC1=CC2=C(C=C1)NC=N2 Chemical compound CCCCCC1=CC2=C(C=C1)NC=N2 TVMPLXPPESHIEQ-UHFFFAOYSA-N 0.000 description 1
- XMTIHMJWJLSUMX-UHFFFAOYSA-N CCCCN(CC1=CC=C(SC)C=C1)C1=CC2=C(C=C1)NC=N2 Chemical compound CCCCN(CC1=CC=C(SC)C=C1)C1=CC2=C(C=C1)NC=N2 XMTIHMJWJLSUMX-UHFFFAOYSA-N 0.000 description 1
- LQRJGNCHUINFGX-UHFFFAOYSA-N CCc1nc(cccc2)c2c(OCc(cc2)ccc2-c(cccc2)c2-c2[nH+][n-]n[nH]2)c1 Chemical compound CCc1nc(cccc2)c2c(OCc(cc2)ccc2-c(cccc2)c2-c2[nH+][n-]n[nH]2)c1 LQRJGNCHUINFGX-UHFFFAOYSA-N 0.000 description 1
- JFYZQDSJSMCXPZ-UHFFFAOYSA-N CN(C)C1=CC=C(CCC2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CN(C)C1=CC=C(CCC2=CC3=C(C=C2)NC=N3)C=C1 JFYZQDSJSMCXPZ-UHFFFAOYSA-N 0.000 description 1
- NJSZPNHKLQMHBE-UHFFFAOYSA-N CN(CC1=CC=C(F)C=C1)CC1=CC=C2NC=NC2=C1 Chemical compound CN(CC1=CC=C(F)C=C1)CC1=CC=C2NC=NC2=C1 NJSZPNHKLQMHBE-UHFFFAOYSA-N 0.000 description 1
- FKISHXSSIBLTBL-UHFFFAOYSA-O CNC(=O)C(N)CCC(=O)O.CNC(=O)C([NH3+])CCC(=O)[O-].CNC(=O)C1CCC(=O)N1.CNC(=O)C1CCC(N)([O-])[NH2+]1.O Chemical compound CNC(=O)C(N)CCC(=O)O.CNC(=O)C([NH3+])CCC(=O)[O-].CNC(=O)C1CCC(=O)N1.CNC(=O)C1CCC(N)([O-])[NH2+]1.O FKISHXSSIBLTBL-UHFFFAOYSA-O 0.000 description 1
- BCLMJDQXDPBCAO-UHFFFAOYSA-N CNC(=O)C(N)CCC(N)=O.CNC(=O)C1CCC(=O)N1.N Chemical compound CNC(=O)C(N)CCC(N)=O.CNC(=O)C1CCC(=O)N1.N BCLMJDQXDPBCAO-UHFFFAOYSA-N 0.000 description 1
- JJYOKMQJJCQUAG-UHFFFAOYSA-N CNC(=O)C(N)CCCC(N)=O.CNC(=O)C1CCCC(=O)N1.N Chemical compound CNC(=O)C(N)CCCC(N)=O.CNC(=O)C1CCCC(=O)N1.N JJYOKMQJJCQUAG-UHFFFAOYSA-N 0.000 description 1
- LJHPGDBLOOZKAE-UHFFFAOYSA-N COC1=C(OC)C=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 Chemical compound COC1=C(OC)C=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 LJHPGDBLOOZKAE-UHFFFAOYSA-N 0.000 description 1
- WNODZKVHLMZOMT-UHFFFAOYSA-N COC1=CC=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 Chemical compound COC1=CC=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 WNODZKVHLMZOMT-UHFFFAOYSA-N 0.000 description 1
- RIGZTVQKRHCTIH-UHFFFAOYSA-N COC1=CC=C(CN(CC2=CC3=C(C=CC=C3)C=C2)C2=CC3=C(C=C2)N=CC3)C=C1 Chemical compound COC1=CC=C(CN(CC2=CC3=C(C=CC=C3)C=C2)C2=CC3=C(C=C2)N=CC3)C=C1 RIGZTVQKRHCTIH-UHFFFAOYSA-N 0.000 description 1
- ABFBZOMBLNOMCV-UHFFFAOYSA-N COC1=CC=C(CN(CC2=CC3=C(C=CC=C3)C=C2)C2=CC3=C(C=C2)NC=C3)C=C1 Chemical compound COC1=CC=C(CN(CC2=CC3=C(C=CC=C3)C=C2)C2=CC3=C(C=C2)NC=C3)C=C1 ABFBZOMBLNOMCV-UHFFFAOYSA-N 0.000 description 1
- GGIDPLVOJVJGTM-UHFFFAOYSA-N COC1=CC=C(CN(CCCC2=CC=CC=C2)C2=CC3=C(C=C2)N=CC3)C=C1 Chemical compound COC1=CC=C(CN(CCCC2=CC=CC=C2)C2=CC3=C(C=C2)N=CC3)C=C1 GGIDPLVOJVJGTM-UHFFFAOYSA-N 0.000 description 1
- UNHRTKFBNLCZJK-UHFFFAOYSA-N COC1=CC=C(CN(CCCC2=CC=CC=C2)C2=CC3=C(C=C2)NC=C3)C=C1 Chemical compound COC1=CC=C(CN(CCCC2=CC=CC=C2)C2=CC3=C(C=C2)NC=C3)C=C1 UNHRTKFBNLCZJK-UHFFFAOYSA-N 0.000 description 1
- STSRMRYLSKLGSS-UHFFFAOYSA-N COC1=CC=C(N(C)CC2=CC=C3NC=NC3=C2)C=C1 Chemical compound COC1=CC=C(N(C)CC2=CC=C3NC=NC3=C2)C=C1 STSRMRYLSKLGSS-UHFFFAOYSA-N 0.000 description 1
- IVTXTIQCTUIKAN-UHFFFAOYSA-N CSC1=CC=C(CCC2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CCC2=CC3=C(C=C2)NC=N3)C=C1 IVTXTIQCTUIKAN-UHFFFAOYSA-N 0.000 description 1
- JFWSODALVYAXCN-UHFFFAOYSA-N CSC1=CC=C(CN(C/C2=N/C3=C(C=CC=C3)S2)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(C/C2=N/C3=C(C=CC=C3)S2)C2=CC3=C(C=C2)NC=N3)C=C1 JFWSODALVYAXCN-UHFFFAOYSA-N 0.000 description 1
- MNGYCRPZACECDZ-UHFFFAOYSA-N CSC1=CC=C(CN(CC(C)C)C2=CC3=C(C=C2)NC=N3)C=C1 Chemical compound CSC1=CC=C(CN(CC(C)C)C2=CC3=C(C=C2)NC=N3)C=C1 MNGYCRPZACECDZ-UHFFFAOYSA-N 0.000 description 1
- VEHSOXAMKKJBIN-UHFFFAOYSA-N Cc1ccc(cc(CNc(cc2)cc3c2[nH]cn3)cc2)c2n1 Chemical compound Cc1ccc(cc(CNc(cc2)cc3c2[nH]cn3)cc2)c2n1 VEHSOXAMKKJBIN-UHFFFAOYSA-N 0.000 description 1
- SLSOFANFMQFJAE-UHFFFAOYSA-N ClC1=CC(CCC2=CC3=C(C=C2)NC=N3)=C(Cl)C=C1 Chemical compound ClC1=CC(CCC2=CC3=C(C=C2)NC=N3)=C(Cl)C=C1 SLSOFANFMQFJAE-UHFFFAOYSA-N 0.000 description 1
- UAGAKKWKZMFTLV-UHFFFAOYSA-N ClC1=CC2=C(C=C1)SC=C2CCC1=CC2=C(C=C1)NC=N2 Chemical compound ClC1=CC2=C(C=C1)SC=C2CCC1=CC2=C(C=C1)NC=N2 UAGAKKWKZMFTLV-UHFFFAOYSA-N 0.000 description 1
- DIQZGSADZWQIAX-UHFFFAOYSA-N ClC1=CC=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 Chemical compound ClC1=CC=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 DIQZGSADZWQIAX-UHFFFAOYSA-N 0.000 description 1
- KIRHJKDRLHQXJF-UHFFFAOYSA-N FC1=C(CCC2=CC3=C(C=C2)NC=N3)C=CC=C1 Chemical compound FC1=C(CCC2=CC3=C(C=C2)NC=N3)C=CC=C1 KIRHJKDRLHQXJF-UHFFFAOYSA-N 0.000 description 1
- GLFYWKDMDIRROQ-UHFFFAOYSA-N FC1=CC(F)=CC(CCC2=CC3=C(C=C2)NC=N3)=C1 Chemical compound FC1=CC(F)=CC(CCC2=CC3=C(C=C2)NC=N3)=C1 GLFYWKDMDIRROQ-UHFFFAOYSA-N 0.000 description 1
- NSHYWSMZNRHYEB-UHFFFAOYSA-N FC1=CC=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 Chemical compound FC1=CC=C(CCC2=CC3=C(C=C2)N=CC3)C=C1 NSHYWSMZNRHYEB-UHFFFAOYSA-N 0.000 description 1
- ALCHVVTYAHQOFY-UHFFFAOYSA-N O=Cc(cc1)cc2c1[nH]cn2 Chemical compound O=Cc(cc1)cc2c1[nH]cn2 ALCHVVTYAHQOFY-UHFFFAOYSA-N 0.000 description 1
- NJCDMYCIZSANBX-UHFFFAOYSA-N [H]C(=O)CC1=CC2=C(C=C1)NC=N2 Chemical compound [H]C(=O)CC1=CC2=C(C=C1)NC=N2 NJCDMYCIZSANBX-UHFFFAOYSA-N 0.000 description 1
- MPWXFHUTQBIAMO-UHFFFAOYSA-N c1nc(cc(cc2)Nc3ccccc3)c2[nH]1 Chemical compound c1nc(cc(cc2)Nc3ccccc3)c2[nH]1 MPWXFHUTQBIAMO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- Sequence Listing which is a part of the present disclosure, includes a computer readable form comprising nucleotide and/or amino acid sequences of the present invention.
- the subject matter of the Sequence Listing is incorporated herein by reference in its entirety.
- the invention relates to inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5).
- QC catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid under liberation of water.
- Glutaminyl cyclase catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (pGlu*) liberating ammonia.
- pGlu* pyroglutamic acid
- Inhibitors of QC are described in WO 2004/098625, WO 2004/098591, WO 2005/039548, WO 2005/075436, WO 2008/055945, WO 2008/055947, WO 2008/055950 and WO2008/065141.
- EP 02 011 349.4 discloses polynucleotides encoding insect glutaminyl cyclase, as well as polypeptides encoded thereby and their use in methods of screening for agents that reduce glutaminyl cyclase activity. Such agents are useful as pesticides.
- WO 00/42022 discloses a series of MEK inhibitors which are claimed to be useful in the treatment of proliferative diseases such as cancer.
- WO 03/077914 discloses a series of MEK inhibitors which are claimed to be useful in the treatment of hyperproliferative diseases such as cancer and inflammation.
- Roy and Bhaduri (1979) Indian J Chem 17B, 164-166 discloses the synthesis of 4,6-dinitro-5-substituted-amino-benzoimidazole compounds.
- Soskic et al (1996) Arzneistoff-Forschung 46(8), 741-746 discloses the synthesis of benzoimidazole ethylamine compounds which are claimed to be useful as dopaminergic ligands.
- Braeuniger et al (1966) Archiv der Pharmazie 299(3), 193-196 discloses a series of benzimidazole compounds which are claimed to be useful as stimulants for plant growth.
- WO 2007/053131 discloses a series of acrylamide derivatives which are claimed to be useful as antibiotic agents.
- WO 01/05770 discloses a series of benzoimidazolone derivatives which are claimed to be useful as cGMP-PDE inhibitors.
- k i or “K I ” and “K D ” are binding constants, which describe the binding of an inhibitor to and the subsequent release from an enzyme. Another measure is the “IC 50 ” value, which reflects the inhibitor concentration, which at a given substrate concentration results in 50% enzyme activity.
- DP IV-inhibitor or “dipeptidyl peptidase IV inhibitor” is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of DP IV or DP IV-like enzymes.
- DP IV-activity is defined as the catalytic activity of dipeptidyl peptidase IV (DP IV) and DP IV-like enzymes. These enzymes are post-proline (to a lesser extent post-alanine, post-serine or post-glycine) cleaving serine proteases found in various tissues of the body of a mammal including kidney, liver, and intestine, where they remove dipeptides from the N-terminus of biologically active peptides with a high specificity when proline or alanine form the residues that are adjacent to the N-terminal amino acid in their sequence.
- PEP-inhibitor or “prolyl endopeptidase inhibitor” is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of prolyl endopeptidase (PEP, prolyl oligopeptidase, POP).
- PEP-activity is defined as the catalytic activity of an endoprotease that is capable to hydrolyze post proline bonds in peptides or proteins where the proline is in amino acid position 3 or higher counted from the N-terminus of a peptide or protein substrate.
- QC as used herein comprises glutaminyl cyclase (QC) and QC-like enzymes.
- QC and QC-like enzymes have identical or similar enzymatic activity, further defined as QC activity.
- QC-like enzymes can fundamentally differ in their molecular structure from QC.
- QC-like enzymes are the glutaminyl-peptide cyclotransferase-like proteins (QPCTLs) from human (GenBank NM — 017659), mouse (GenBank BC058181), Macaca fascicularis (GenBank AB168255), Macaca mulatta (GenBank XM — 001110995), Canis familiaris (GenBank XM — 541552), Rattus norvegicus (GenBank XM — 001066591), Mus musculus (GenBank BC058181) and Bos taurus (GenBank BT026254).
- QPCTLs glutaminyl-peptide cyclotransferase-like proteins
- QC activity is defined as intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (pGlu*) or of N-terminal L-homoglutamine or L- ⁇ -homoglutamine to a cyclic pyro-homoglutamine derivative under liberation of ammonia. See therefore schemes 1 and 2.
- EC as used herein comprises the activity of QC and QC-like enzymes as glutamate cyclase (EC), further defined as EC activity.
- EC activity as used herein is defined as intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid (pGlu*) by QC. See therefore scheme 3.
- glutaminyl cyclase inhibitor is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of glutaminyl cyclase (QC) or its glutamyl cyclase (EC) activity.
- the subject method and medical use utilize an agent with an IC 50 for QC inhibition of 10 ⁇ M or less, more preferably of 1 ⁇ M or less, even more preferably of 0.1 ⁇ M or less or 0.01 ⁇ M or less, or most preferably 0.001 ⁇ M or less.
- IC 50 for QC inhibition 10 ⁇ M or less, more preferably of 1 ⁇ M or less, even more preferably of 0.1 ⁇ M or less or 0.01 ⁇ M or less, or most preferably 0.001 ⁇ M or less.
- inhibitors with K, values in the lower micromolar, preferably the nanomolar and even more preferably the picomolar range are contemplated.
- active agents are described herein, for convenience, as “QC inhibitors”, it will be understood that such nomenclature is not intending to limit the subject of the invention to a particular mechanism of action.
- the QC inhibitors of the subject method or medical use will be small molecules, e.g., with molecular weights of 500 g/mole or less, 400 g/mole or less, preferably of 350 g/mole or less, and even more preferably of 300 g/mole or less and even of 250 g/mole or less.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
- the term “pharmaceutically acceptable” embraces both human and veterinary use:
- pharmaceutically acceptable embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care.
- alkyl denotes a C 1-12 alkyl group, suitably a C 1-8 alkyl group, e.g. C 1-6 alkyl group, e.g. C 1-4 alkyl group.
- Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g n-butyl, iso-butyl, sec-butyl and tert-butyl), pentyl (e.g. n-pentyl), hexyl (e.g.
- alk for example in the expressions “alkoxy”, “haloalkyl” and “thioalkyl” should be interpreted in accordance with the definition of “alkyl”.
- alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hexoxy (e.g. n-hexoxy), heptoxy (e.g.
- n-heptoxy n-heptoxy
- octoxy e.g. n-octoxy
- exemplary thioalkyl groups include methylthio-.
- exemplary haloalkyl groups include fluoroalkyl e.g. CF 3 .
- alkenyl denotes a C 2-12 alkenyl group, suitably a C 2-6 alkenyl group, e.g. a C 2-4 alkenyl group, which contains at least one double bond at any desired location and which does not contain any triple bonds.
- Alkenyl groups may be straight chain or branched.
- Exemplary alkenyl groups including one double bond include propenyl and butenyl.
- Exemplary alkenyl groups including two double bonds include pentadienyl, e.g. (1E,3E)-pentadienyl.
- alkynyl denotes a C 2-12 alkynyl group, suitably a C 2-6 alkynyl group, e.g. a C 2-4 alkynyl group, which contains at least one triple bond at any desired location and may or may not also contain one or more double bonds.
- Alkynyl groups may be straight chain or branched.
- Exemplary alkynyl groups include propynyl and butynyl.
- alkylene denotes a chain of formula —(CH 2 ) n — wherein n is an integer e.g. 2-5, unless specifically limited.
- cycloalkyl denotes a C 3-10 cycloalkyl group (i.e. 3 to 10 ring carbon atoms), more suitably a C 3-8 cycloalkyl group, e.g. a C 3-6 cycloalkyl group.
- exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- a most suitable number of ring carbon atoms is three to six.
- heterocyclyl refers to a carbocyclyl group wherein one or more (e.g. 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O.
- a specific example of a heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or more particularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O.
- heterocyclyl groups containing one hetero atom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two hetero atoms include morpholine, piperazine, dioxolane and dioxane.
- a further specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S and O.
- An example of such a group is dihydropyranyl (e.g. 3,4-dihydro-2H-pyran-2-yl-).
- aryl denotes a C 6-12 aryl group, suitably a C 6-10 aryl group, more suitably a C 6-8 aryl group.
- Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings).
- An example of a typical aryl group with one aromatic ring is phenyl.
- An example of a typical aryl group with two aromatic rings is naphthyl.
- heteroaryl denotes an aryl residue, wherein one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O, or else a 5-membered aromatic ring containing one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms selected from N, S and O.
- exemplary monocyclic heteroaryl groups having one heteroatom include: five membered rings (e.g. pyrrole, furan, thiophene); and six membered rings (e.g.
- pyridine such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl
- exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g. pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-yl imidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine, pyrazine).
- Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1,2,3-triazole and 1,2,4-triazole.
- Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole.
- Exemplary bicyclic heteroaryl groups include: indole (e.g. indol-6-yl), benzofuran, benzthiophene, quinoline, isoquinoline, indazole, benzimidazole, benzthiazole, quinazoline and purine.
- alkylaryl unless specifically limited, denotes an aryl residue which is connected via an alkylene moiety e.g. a C 1-4 alkylene moiety.
- alkylheteroaryl denotes a heteroaryl residue which is connected via an alkylene moiety e.g. a C 1-4 alkylene moiety.
- halogen or “halo” comprises fluorine (F), chlorine (Cl) and bromine (Br).
- amino refers to the group —NH 2 .
- phenyl substituted by phenyl refers to biphenyl.
- benzimidazolyl is shown as benzimidazol-5-yl, which is represented as:
- the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
- the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers
- these isomers may be separated by conventional techniques such as preparative chromatography.
- the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
- the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as ( ⁇ )-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
- the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
- Salts and solvates of the compounds of formula (I) and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable.
- salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts and solvates.
- Suitable salts according to the invention include those formed with both organic and inorganic acids or bases.
- Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic or naphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl
- Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.
- some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention.
- some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
- the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
- the present invention further includes within its scope prodrugs of the compounds of this invention.
- prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound.
- the term “administering” shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds, but which converts to the above specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
- any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, fully incorporated herein by reference.
- the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
- composition is intended to encompass a product comprising the claimed compounds in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the claimed compounds.
- suitable carriers and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
- suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
- Carriers which can be added to the mixture, include necessary and inert pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, disintegrating agents, dyes and coloring agents.
- Soluble polymers as targetable drug carriers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolyllysine substituted with palmitoyl residue.
- the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- Het represents a bicyclic heteroaryl group
- the first compound of the proviso, 5-diethylamino-benzimidazolyl is a commercially available compound having no associated therapeutic indication.
- the fifth compound of the proviso, (1H-benzo[d]imidazol-5-yl)-N-methylmethanamine is referred to as an intermediate used in the preparation of Example 76 in WO 2007/053131.
- Preparation 12 The sixth compound of the proviso, 4-(benzoimidazol-5-ylamino)-3-nitrobenzonitrile, is referred to as Preparation 12 (22) in WO 01/05770.
- the seventh compound of the proviso, 6-(benzimidazol-5-yl)amino-5-nitronicotinonitrile is referred to as Preparation 9 (8) in WO 01/05770.
- the ninth compound of the proviso, 5-amino-6-(benzimidazol-5-yl)aminonicotinonitrile is referred to as Preparation 15 (58) in WO 01/05770.
- Het represents a bicyclic heteroaryl group
- cycloalkyl and heterocyclyl When cycloalkyl and heterocyclyl are substituted, they are typically substituted by 1 or 2 substituents (e.g. 1 substituent). Typically the substituent is methyl. More typically carbocyclyl and heterocyclyl groups are unsubstituted.
- aryl, Het and heteroaryl When aryl, Het and heteroaryl are substituted, they are typically substituted by 1, 2 or 3 (e.g. 1 or 2) substituents.
- Substituents for aryl, Het and heteroaryl are selected from C 1-6 alkyl (e.g. methyl), C 2-6 alkenyl (e.g. buten-3-yl), C 2-6 alkynyl (e.g. butyn-3-yl), C 1-6 haloalkyl (e.g. fluoromethyl, trifluoromethyl), —C 1-6 thioalkyl (e.g. —S-methyl), —SOC 1-4 alkyl (e.g. —SOmethyl), —SO 2 C 1-4 alkyl (e.g.
- —SO 2 -methyl C 1-6 alkoxy- (e.g. methoxy, ethoxy), —O—C 3-8 cycloalkyl (e.g. —O-cyclopentyl), C 3-8 cycloalkyl (e.g. cyclopropyl, cyclohexyl), —SO 2 C 3-8 cycloalkyl (e.g. —SO 2 cyclohexyl), —SOC 3-6 cycloalkyl (e.g. —SOcyclopropyl), C 3-6 alkenyloxy- (e.g. —O-buten-2-yl), C 3-6 alkynyloxy- (e.g.
- —O-buten-2-yl —C(O)C 1-6 alkyl (e.g. —C(O)ethyl), —C(O)OC 1-6 alkyl (e.g. —C(O)O-methyl), C 1-6 alkoxy-C 1-6 alkyl- (e.g. methoxy-ethyl-), nitro, halogen (e.g. fluoro, chloro, bromo), cyano, hydroxyl, —C(O)OH, —NH 2 , —NHC 1-4 alkyl (e.g. —NHmethyl), —N(C 1-4 alkyl)(C 1-4 alkyl) (e.g.
- substituents will be selected from C 1-6 alkyl (e.g. methyl), C 1-6 haloalkyl (e.g. C 1-6 -fluoroalkyl, e.g. CF 3 ), C 1-6 alkoxy (e.g. OMe), halogen and hydroxy.
- R 1 or R 2 represents —C 1-6 alkylcycloalkyl, —C 1-6 alkylaryl or —C 1-6 alkyl-Het, examples wherein alkyl is branched include:
- R 1 or R 2 represents aryl or —C 1-6 alkylaryl
- said aryl suitably represents optionally substituted phenyl.
- exemplary substituted phenyl groups for R 1 and R 2 include 2-bromophenyl, 2-bromo-4-fluorophenyl-, 2-bromo-5-fluorophenyl-, 2-chlorophenyl-, 2-fluorophenyl-, 3-chlorophenyl-, 3-bromophenyl-, 3-fluorophenyl-, 4-chlorophenyl-, 4-fluorophenyl-, 4-bromophenyl-, 4-bromo-2-fluorophenyl, 2,3-dichlorophenyl-, 2,3-difluorophenyl-, 2,3,4-trifluorophenyl, 2,4-dichlorophenyl-, 2,4-difluororophenyl-, 2,4,6-trifluorophenyl-, 2,5
- R 2 may represent unsubstituted phenyl-.
- substituted phenyl groups include 2,3-difluoro-4-methylphenyl, 2-fluoro-5-(trifluoromethyl)phenyl-, 2-hydroxy-3-methoxyphenyl-, 2-hydroxy-5-methylphenyl-, 3-fluoro-4-(trifluoromethyl)phenyl-, 3-fluoro-5-(trifluoromethyl)phenyl-, 2-fluoro-4-(trifluoromethyl)phenyl-, 2-fluoro-3-(methyl)phenyl-, 3-fluoro-4-(methoxy)phenyl-, 3-hydroxy-4-methoxyphenyl-, 4-chloro-3-(trifluoromethyl)phenyl-, 4-chloro-3-methylphenyl, 4-bromo-4-ethylphenyl, 2,3,5,6-tetrafluoro-4-(methyl)phenyl-, 2,6-difluoro-4-
- R 1 or R 2 represents aryl or —C 1-6 alkylaryl
- said aryl suitably represents optionally substituted naphthyl.
- Examples include unsubstituted naphthyl (e.g. naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl) as well as substituted naphthyl (e.g. 4-methyl-naphthalen-2-yl-, 5-methyl-naphthalen-3-yl-, 7-methyl-naphthalen-3-y- and 4-fluoro-naphthalen-2-yl-).
- unsubstituted naphthyl e.g. naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl
- substituted naphthyl e.g. 4-methyl-naphthalen-2-yl-, 5-methyl-naphthalen-3-yl-, 7-methyl-naphthalen-3-
- R 1 or R 2 represents cycloalkyl or —C 1-6 alkylcycloalkyl said cycloalkyl suitably represents optionally substituted cycloalkyl.
- cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- substituted carbocyclyl include 2-methyl-cyclohexyl-, 3-methyl-cyclohexyl- and 4-methyl-cyclohexyl-.
- R 1 or R 2 represents —C 1-6 alkyl-Het
- suitable examples of Het include bicyclic rings (e.g. 9 or 10 membered rings) which may optionally be substituted.
- Example 9 membered rings include 1H-indolyl (e.g. 1H-indol-3-yl, 1H-indol-5-yl), benzothiophenyl (e.g. benzo[b]thiophen-3-yl, particularly 2-benzo[b]thiophen-3-yl), benzo[1,2,5]-oxadiazolyl (e.g. benzo[1,2,5]-oxadiazol-5-yl), benzo[d]thiazolyl (e.g.
- Example 10 membered rings include quinolinyl (e.g. quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, quinolin-8-yl).
- Specific substituents that may be mentioned are one or more e.g. 1, 2 or 3 groups selected from halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-).
- Example substituted 9-membered rings include 1-methyl-1H-indol-3-yl, 2-methyl-1H-indol-3-yl, 6-methyl-1H-indol-3-yl and 5-chlorobenzo[b]thiophen-3-yl.
- Example substituted 10 membered rings include 2-chloro-quinolin-3-yl, 8-hydroxy-quinolin-2-yl, 2-methyl-quinolin-6-yl, oxo-chromenyl (e.g. 4-oxo-4H-chromen-3-yl) and 6-methyl-4-oxo-4H-chromen-3-yl.
- R 1 or R 2 represents aryl or —C 1-6 alkylaryl substituted by phenyl or aryl or —C 1-6 alkylaryl substituted by a heteroaryl group (such as a monocyclic heteroaryl), in which any of aforesaid phenyl and heteroaryl groups may optionally be substituted, typically the aryl ring connected directly to the nitrogen atom is unsubstituted and the terminal phenyl ring or the monocyclic heteroaryl ring is optionally substituted by one, two or three substitutents (e.g. one or two, e.g. one). Typically the terminal phenyl or monocyclic heteroaryl group is unsubstituted. Typically the terminal phenyl or monocyclic heteroaryl group substitutes the aryl ring (i.e. phenyl) at the 4-position.
- a heteroaryl group such as a monocyclic heteroaryl
- R 1 or R 2 represents aryl or —C 1-6 alkylaryl substituted by phenyl in which any of aforesaid aryl or phenyl groups may optionally be substituted, examples include -biphenyl-4-yl and —CH 2 -biphenyl-4-yl.
- R 1 or R 2 represents aryl or —C 1-6 alkylaryl substituted by a monocyclic heteroaryl group, in which any of aforesaid aryl and heteroaryl groups may optionally be substituted, examples include (4-thiophen-2-yl)-benzyl- and (4-(oxazol-5-yl)phenyl-.
- R 1 or R 2 represents aryl or —C 1-6 alkylaryl substituted by phenyloxy in which any of aforesaid aryl and phenyloxy groups may optionally be substituted
- examples include 4-benzyloxy-phenyl-, 4-(3-methylbenzyloxy)phenyl- and 4-(4-methylbenzyloxy)phenyl-.
- R 1 or R 2 represents aryl or —C 1-6 alkylaryl fused to heterocyclyl
- examples include benzo[1,3]dioxo-4-yl-, 3,4-dihydro-benzo[1,4]dioxepin-9-yl and 2,3-dihydro-benzo[1,4]dioxin-4-yl-.
- R 1 represents hydrogen, C 1-6 alkyl (e.g. methyl), —C 1-6 alkylaryl (e.g. —CH 2 -phenyl, —(CH 2 ) 2 -phenyl, —(CH 2 ) 3 -phenyl or —CH 2 -naphthyl), —C 1-6 alkyl-Het (e.g. —CH 2 -benzothiazolyl, —CH 2 -benzothiadiazolyl, —CH 2 -benzothiophenyl, —CH 2 -quinolinyl), —C 1-6 alkylaryl fused to heterocyclyl (e.g. dihydrobenzodioxepinyl) or —C 1-6 alkylaryl substituted by heteroaryl (e.g. —CH 2 -phenyl substituted by thiophenyl).
- C 1-6 alkyl e.g. methyl
- C 1-6 alkylaryl
- R 2 represents —C 1-6 alkyl (e.g. butyl, pentan-2-yl or isobutyl), -aryl (e.g. phenyl), —C 1-6 alkylaryl (e.g. —CH 2 -phenyl, —CH 2 -naphthyl, —CH(CH 3 )-phenyl, —(CH 2 ) 2 -phenyl or —(CH 2 ) 3 -phenyl), —C 1-6 alkylcycloalkyl (e.g. —CH 2 -cyclohexyl), —C 1-6 alkyl-Het (e.g.
- R 2 represents a group other than —C 1-6 alkyl.
- R 2 represents -aryl (e.g. phenyl), —C 1-6 alkylaryl (e.g.
- heterocyclyl e.g. dihydrobenz
- R 1 represents hydrogen and R 2 represents C 1-6 alkyl (e.g. butyl, pentan-2-yl or isobutyl), -aryl (e.g. phenyl), —C 1-6 alkylaryl (e.g. —CH 2 -phenyl, —CH 2 -naphthyl, —CH(CH 3 )-phenyl or —(CH 2 ) 2 -phenyl), —C 1-6 alkylcycloalkyl (e.g. —CH 2 -cyclohexyl), —C 1-6 alkyl-Het (e.g.
- halogen e.g. chlorine, fluorine or bromine
- C 1-6 alkoxy e.g. methoxy
- C 1-6 alkyl e.g.
- —C 1-6 thioalkyl e.g. thiomethyl
- —N(C 1-4 alkyl)(C 1-4 alkyl) e.g. —NMe 2
- Het group is optionally substituted by one or more halogen (e.g. chlorine) or C 1-6 alkyl (e.g. methyl) groups.
- R 1 represents C 1-6 alkyl (e.g. methyl) and R 2 represents -aryl (e.g. phenyl) or —C 1-6 alkylaryl (e.g. —CH 2 -phenyl); wherein said phenyl group is optionally substituted by one or more halogen (e.g. fluorine) or C 1-6 alkoxy (e.g. methoxy) groups.
- halogen e.g. fluorine
- C 1-6 alkoxy e.g. methoxy
- R 1 represents —C 1-6 alkylaryl (e.g. —CH 2 -phenyl, —(CH 2 ) 2 -phenyl, —(CH 2 ) 3 -phenyl or —CH 2 -naphthyl) and R 2 represents —C 1-6 alkylaryl (e.g. —CH 2 -phenyl or —CH 2 -naphthyl), —C 1-6 alkylcycloalkyl (e.g. —CH 2 -cyclohexyl) or —C 1-6 alkyl (e.g.
- phenyl groups are optionally substituted by one or more halogen (e.g. chlorine, fluorine or bromine), cyano, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl, t-butyl), C 1-6 alkoxy (e.g. methoxy), —C 1-6 thioalkyl (e.g. thiomethyl) or —N(C 1-4 alkyl)(C 1-4 alkyl) (e.g. —NMe 2 ) groups.
- halogen e.g. chlorine, fluorine or bromine
- C 1-6 alkyl e.g. methyl, ethyl, isopropyl, t-butyl
- C 1-6 alkoxy e.g. methoxy
- —C 1-6 thioalkyl e.g. thiomethyl
- N(C 1-4 alkyl)(C 1-4 alkyl) e.g. —
- R 1 and R 2 both represent —C 1-6 alkylaryl (e.g. —CH 2 -phenyl, —(CH 2 ) 2 -phenyl, —(CH 2 ) 3 -phenyl or —CH 2 -naphthyl); wherein said phenyl groups are optionally substituted by one or more halogen (e.g. chlorine, fluorine or bromine), cyano, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl, t-butyl), C 1-6 alkoxy (e.g. methoxy), —C 1-6 thioalkyl (e.g. thiomethyl) or —N(C 1-4 alkyl)(C 1-4 alkyl) (e.g. —NMe 2 ) groups.
- halogen e.g. chlorine, fluorine or bromine
- C 1-6 alkyl e.g. methyl, ethyl,
- R 1 and R 2 both represent —C 1-6 alkylaryl fused to heterocyclyl (e.g. dihydrobenzodioxepinyl).
- R 1 and R 2 both represent —C 1-6 alkylaryl substituted by heteroaryl (e.g. —CH 2 -phenyl substituted by thiophenyl).
- R 1 represents —C 1-6 alkyl-Het (e.g. —CH 2 -benzothiazolyl, —CH 2 -benzothiadiazolyl, —CH 2 -benzothiophenyl, —CH 2 -quinolinyl) and R 2 represents —C 1-6 alkyl-Het (e.g. —CH 2 -benzothiazolyl, —CH 2 -benzothiadiazolyl, —CH 2 -benzothiophenyl, —CH 2 -quinolinyl) or —C 1-6 alkylcarbocyclyl (e.g.
- —CH 2 -phenyl wherein said Het groups are optionally substituted by one or more halogen (e.g. chlorine) or C 1-6 alkyl (e.g. methyl) groups; and wherein said phenyl group is optionally substituted by one or more —C 1-6 thioalkyl (e.g. thiomethyl), C 1-6 alkyl (e.g. ethyl), C 1-6 alkoxy (e.g. methoxy), halogen (e.g. chlorine) or —N(C 1-4 alkyl)(C 1-4 alkyl) (e.g. —NMe 2 ) groups.
- halogen e.g. chlorine
- C 1-6 alkyl e.g. methyl
- phenyl group is optionally substituted by one or more —C 1-6 thioalkyl (e.g. thiomethyl), C 1-6 alkyl (e.g. ethyl), C 1-6 alkoxy (e
- R 1 and R 2 both represent —C 1-6 alkyl-Het (e.g. —CH 2 -benzothiazolyl, —CH 2 -benzothiadiazolyl, —CH 2 -benzothiophenyl, —CH 2 -quinolinyl); wherein said Het groups are optionally substituted by one or more halogen (e.g. chlorine) or C 1-6 alkyl (e.g. methyl) groups.
- halogen e.g. chlorine
- C 1-6 alkyl e.g. methyl
- R 1 represents aryl (e.g. phenyl) and R 2 represents —C 1-6 alkylaryl (e.g. —CH 2 -phenyl).
- X represents a bond or a —CH 2 -group. More suitably, X represents a bond.
- X represents a —(CH 2 ) m -group, m suitably represents an integer selected from 1 or 2, more suitably 1.
- n represents an integer from 0 to 2, more suitably 0 or 1. In one embodiment, n represents 0.
- R a substituent will be located on the phenyl ring of the benzimidazolyl group.
- Process (a) typically comprises reaction in a suitable solvent, such as THF in the presence of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, Pd 2 dba 3 and lithiumbis(trimethylsilyl)amide, followed by heating under an Argon atmosphere to 65° C. for 24 h.
- a suitable solvent such as THF
- Process (b) typically comprises addition of a compound of formula (III) to a suitable reducing agent, such as sodium borohydride, in a suitable solvent, such as ethanol at room temperature.
- a suitable reducing agent such as sodium borohydride
- a suitable solvent such as ethanol at room temperature.
- Process (c) typically comprises reaction in a suitable solvent, such as methanol followed by addition of a suitable reducing agent, such as sodium borohydride.
- a suitable solvent such as methanol
- a suitable reducing agent such as sodium borohydride
- Process (d) typically comprises dissolving the compound of formula (IV) in a suitable solvent, such as DMF followed by treatment with the compound of formula L 2 -R 2 and potassium carbonate.
- a suitable solvent such as DMF
- Process (f) typically comprises dissolving the compound of formula (VI) in a suitable solvent, such as tetrahydrofuran, followed by addition of the compound of formula HNR 1 R 2 , NaBH(AcO) 3 and ethanol.
- a suitable solvent such as tetrahydrofuran
- R 2 , n and R a are as defined for compounds of formula (I), with a compound of formula L 4 —R 1a , wherein L 4 represents a suitable leaving group such as bromine and R 1a represents an R 1 group as defined for compounds of formula (I) other than hydrogen.
- This interconversion typically comprises dissolving the compound of formula (V) in a suitable solvent, such as DMF followed by treatment with the compound of formula L 4 —R 1a and potassium carbonate.
- a suitable solvent such as DMF
- Novel intermediates are claimed as an aspect of the present invention.
- Physiological substrates of QC (EC) in mammals are, e.g. amyloid beta-peptides (3-40), (3-42), (11-40 and (11-42), ABri, ADan, Gastrin, Neurotensin, FPP, CCL 2, CCL 7, CCL 8, CCL 16, CCL 18, Fractalkine, Orexin A, [Gln 3 ]-glucagon(3-29), [Gln 5 ]-substance P(5-11) and the peptide QYNAD.
- Table 1 The compounds and/or combinations according to the present invention and pharmaceutical compositions comprising at least one inhibitor of QC (EC) are useful for the treatment of conditions that can be treated by modulation of QC activity.
- Neurotensin QLYENKPRRP YIL Neurotensin plays an endocrine Swiss-Prot: or paracrine role in the P30990 regulation of fat metabolism. It causes contraction of smooth muscle.
- FPP QEP amide A tripeptide related to thyrotrophin releasing hormone (TRH), is found in seminal plasma. Recent evidence obtained in vitro and in vivo showed that FPP plays an important role in regulating sperm fertility.
- TRH QHP amide TRH functions as a regulator of Swiss-Prot: the biosynthesis of TSH in the P20396 anterior pituitary gland and as a neurotransmitter/neuromodulator in the central and peripheral nervous systems.
- GnRH QHWSYGL RP(G) amide Stimulates the secretion of Swiss-Prot: gonadotropins; it stimulates the P01148 secretion of both luteinizing and follicle-stimulating hormones.
- CCL16 small QPKVPEW VNTPSTCCLK Shows chemotactic activity for inducible YYEKVLPRRL VVGYRKALNC lymphocytes and monocytes but not cytokine A16 HLPAIIFVTK RNREVCTNPN neutrophils. Also shows potent Swiss-Prot: DDWVQEYIKD PNLPLLPTRN myelosuppressive activity, O15467 LSTVKIITAK NGQPQLLNSQ suppresses proliferation of myeloid progenitor cells. Recombinant SCYA16 shows chemotactic activity for monocytes and THP-1 monocytes, but not for resting lymphocytes and neutrophils.
- CCL2 (MCP-1, QPDAINA PVTCCYNFTN Chemotactic factor that attracts small inducible RKISVQRLAS YRRITSSKCP monocytes and basophils but cytokine A2) KEAVIFKTIV AKEICADPKQ not neutrophils or eosinophils.
- CCL18 small QVGTNKELC CLVYTSWQIP Chemotactic factor that attracts inducible QKFIVDYSET SPQCPKPGVI lymphocytes but not monocytes cytokine A18
- LLTKRGRQIC ADPNKKWVQK or granulocytes May be Swiss-Prot: YISDLKLNA involved in B cell migration into P55774 B cell follicles in lymph nodes.
- naive T lymphocytes toward dendritic cells and activated macrophages in lymph nodes has chemotactic activity for naive T cells, CD4+ and CD8+ T cells and thus may play a role in both humoral and cell-mediated immunity responses.
- Fractalkine QHHGVT KCNITCSKMT The soluble form is chemotactic (neurotactin) SKIPVALLIH YQQNQASCGK for T cells and monocytes, but Swiss-Prot: RAIILETRQH RLFCADPKEQ not for neutrophils.
- the P78423 WVKDAMQHLD RQAAALTRNG membrane-bound form promotes GTFEKQIGEV KPRTTPAAGG adhesion of those leukocytes MDESVVLEPE ATGESSSLEP to endothelial cells. May play TPSSQEAQRA LGTSPELPTG a role in regulating leukocyte VTGSSGTRLP PTPKAQDGGP adhesion and migration processes VGTELFRVPP VSTAATWQSS at the endothelium binds to APHQPGPSLW AEAKTSEAPS CX3CR1.
- Augments Swiss-Prot KWVQDFMKHL DKKTQTPKL monocyte anti-tumor activity. P80098 also induces the release of gelatinase B.
- This protein can bind heparin. Binds to CCR1, CCR2 and CCR3.
- Orexin A QPLPDCCRQK TCSCRLYELL Neuropeptide that plays a (Hypocretin-1) HGAGNHAAGI LTL significant role in the regulation Swiss-Prot of food intake and sleep O43612 wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. It plays also a broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids.
- Orexin-A binds to both OX1R and OX2R with a high affinity.
- Substance P RPK PQQFFGLM Belongs to the tachykinins.
- Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles.
- QYNAD Gln-Tyr-Asn-Ala-Asp Acts on voltage-gated sodium channels.
- Glutamate is found in positions 3, 11 and 22 of the amyloid O-peptide.
- the mutation from glutamic acid (E) to glutamine (Q) in position 22 has been described as the so called Dutch type cerebroarterial amyloidosis mutation.
- ⁇ -amyloid peptides with a pyroglutamic acid residue in position 3, 11 and/or 22 have been described to be more cytotoxic and hydrophobic than the amyloid O-peptides 1-40(42/43) (Saido T. C. 2000 Medical Hypotheses 54(3): 427-429).
- the multiple N-terminal variations e.g. Abeta(3-40), Abeta(3-42), Abeta(11-40) and Abeta (11-42) can be generated by the 6-secretase enzyme 6-site amyloid precursor protein-cleaving enzyme (BACE) at different sites (Huse J. T. et al. 2002 J. Biol. Chem. 277 (18): 16278-16284), and/or by aminopeptidase or dipeptidylaminopeptidase processing from the full length peptides Abeta(1-40) and Abeta(1-42). In all cases, cyclization of the then N-terminal occurring glutamic acid residue is catalyzed by QC.
- BACE 6-site amyloid precursor protein-cleaving enzyme
- Transepithelial transducing cells particularly the gastrin (G) cell, co-ordinate gastric acid secretion with the arrival of food in the stomach.
- G gastrin
- Biosynthetic precursors and intermediates are putative growth factors; their products, the amidated gastrins, regulate epithelial cell proliferation, the differentiation of acid-producing parietal cells and histamine-secreting enterochromaffin-like (ECL) cells, and the expression of genes associated with histamine synthesis and storage in ECL cells, as well as acutely stimulating acid secretion.
- Gastrin also stimulates the production of members of the epidermal growth factor (EGF) family, which in turn inhibit parietal cell function but stimulate the growth of surface epithelial cells.
- EGF epidermal growth factor
- Plasma gastrin concentrations are elevated in subjects with Helicobacter pylori , who are known to have increased risk of duodenal ulcer disease and gastric cancer (Dockray, G. J. 1999 J Physiol 15 315-324).
- the peptide hormone gastrin released from antral G cells, is known to stimulate the synthesis and release of histamine from ECL cells in the oxyntic mucosa via CCK-2 receptors.
- the mobilized histamine induces acid secretion by binding to the H(2) receptors located on parietal cells.
- gastrin in both its fully amidated and less processed forms (progastrin and glycine-extended gastrin), is also a growth factor for the gastrointestinal tract. It has been established that the major trophic effect of amidated gastrin is for the oxyntic mucosa of stomach, where it causes increased proliferation of gastric stem cells and ECL cells, resulting in increased parietal and ECL cell mass.
- the major trophic target of the less processed gastrin e.g. glycine-extended gastrin
- the colonic mucosa Kelman, T. J. and Chen, D. 2000 Regul Pept 9337-44.
- Neurotensin is a neuropeptide implicated in the pathophysiology of schizophrenia that specifically modulates neurotransmitter systems previously demonstrated to be misregulated in this disorder.
- Clinical studies in which cerebrospinal fluid (CSF) NT concentrations have been measured revealed a subset of schizophrenic patients with decreased CSF NT concentrations that are restored by effective antipsychotic drug treatment.
- CSF cerebrospinal fluid
- Considerable evidence also exists concordant with the involvement of NT systems in the mechanism of action of antipsychotic drugs.
- the behavioral and biochemical effects of centrally administered NT remarkably resemble those of systemically administered antipsychotic drugs, and antipsychotic drugs increase NT neurotransmission. This concatenation of findings led to the hypothesis that NT functions as an endogenous antipsychotic.
- FPP Fertilization promoting peptide
- TRH thyrotrophin releasing hormone
- FPP and adenosine have been shown to stimulate cAMP production in uncapacitated cells but inhibit it in capacitated cells, with FPP receptors somehow interacting with adenosine receptors and G proteins to achieve regulation of AC. These events affect the tyrosine phosphorylation state of various proteins, some being important in the initial “switching on”, others possibly being involved in the acrosome reaction itself.
- Calcitonin and angiotensin II also found in seminal plasma, have similar effects in vitro on uncapacitated spermatozoa and can augment responses to FPP. These molecules have similar effects in vivo, affecting fertility by stimulating and then maintaining fertilizing potential.
- CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18 and fractalkine play an important role in pathophysiological conditions, such as suppression of proliferation of myeloid progenitor cells, neoplasia, inflammatory host responses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, humoral and cell-mediated immunity responses, leukocyte adhesion and migration processes at the endothelium, inflammatory bowel disease, restenosis, pulmonary fibrosis, pulmonary hypertention, liver fibrosis, liver cirrhosis, nephrosclerosis, ventricular remodeling, heart failure, arteriopathy after organ transplantations and failure of vein grafts.
- pathophysiological conditions such as suppression of proliferation of myeloid progenitor cells, neoplasia, inflammatory host responses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, humor
- MCP-1 might also play a role in gestosis (Katabuchi, H., et al., (2003) Med Electron Microsc. 36, 253-262), as a paracrine factor in tumor development (Ohta, M., et al., (2003) Int. J Oncol. 22, 773-778; Li, S., et al., (2005) J. Exp. Med 202, 617-624), neuropathic pain (White, F. A., et al., (2005) Proc. Natl. Acad. Sci. U.S.A ) and AIDS (Park, I. W., Wang, J. F., and Groopman, J. E. (2001) Blood 97, 352-358; Coll, B., et al., (2006) Cytokine 34, 51-55).
- MCP-1 levels are increased in CSF of AD patients and patients showing mild cognitive impairment (MCI) (Galimberti, D., et al., (2006) Arch. Neurol. 63, 538-543). Furthermore, MCP-1 shows an increased level in serum of patients with MC1 and early AD (Clerici, F., et al., (2006) Neurobiol. Aging 27, 1763-1768).
- MCI mild cognitive impairment
- cytotoxic T lymphocyte peptide-based vaccines against hepatitis B, human immunodeficiency virus and melanoma were recently studied in clinical trials.
- This peptide is a Melan-A/MART-1 antigen immunodominant peptide analog, with an N-terminal glutamic acid. It has been reported that the amino group and gamma-carboxylic group of glutamic acids, as well as the amino group and gamma-carboxamide group of glutamines, condense easily to form pyroglutamic derivatives.
- Orexin A is a neuropeptide that plays a significant role in the regulation of food intake and sleep-wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. It plays also a role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids.
- QYNAD is a substrate of the enzyme glutaminyl cyclase (QC, EC 2.3.2.5), which is also present in the brain of mammals, especially in human brain. Glutaminyl cyclase catalyzes effectively the formation of pEYNAD from its precursor QYNAD.
- the present invention provides the use of the compounds of formula (I) for the preparation of a medicament for the prevention or alleviation or treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, Huntington's disease, Kennedy's disease, ulcer disease, duodenal cancer with or w/o Helicobacter pylori infections, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infections, pathogenic psychotic conditions, schizophrenia, infertility, neoplasia, inflammatory host responses, cancer, malign metastasis, melanoma, psoriasis, rheumatoid arthritis, atherosclerosis, pancreatitis, restenosis, impaired humoral and cell-mediated immune responses, leukocyte adhesion and migration processes in the endothelium, impaired food intake, impaired sleep-wake
- a QC inhibitor according to the present invention can lead to suppression of male fertility.
- the present invention provides the use of inhibitors of QC (EC) activity in combination with other agents, especially for the treatment of neuronal diseases, artherosclerosis and multiple sclerosis.
- the present invention also provides a method of treatment of the aforementioned diseases comprising the administration of a therapeutically active amount of at least one compound of formula (I) to a mammal, preferably a human.
- said method and corresponding uses are for the treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, Parkinson's disease and Chorea Huntington, comprising the administration of a therapeutically active amount of at least one compound of formula (I) to a mammal, preferably a human.
- a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, Parkinson's disease and Chorea Huntington, comprising the administration of a therapeutically active amount of at least one compound of formula (I) to a mammal, preferably a human.
- the present invention provides a method of treatment and corresponding uses for the treatment of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis.
- the present invention provides a composition, preferably a pharmaceutical composition, comprising at least one QC inhibitor optionally in combination with at least one other agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
- at least one QC inhibitor optionally in combination with at least one other agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
- said QC inhibitor is a compound of formula (I) of the present invention.
- the aforementioned other agent is selected from the group consisting of beta-amyloid antibodies, cysteine protease inhibitors, PEP-inhibitors, LiCl, acetylcholinesterase (AChE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of aminopeptidases, preferably inhibitors of dipeptidyl peptidases, most preferably DP IV inhibitors; inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents, MCP-1 antagonists or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 57
- the other agent may be, for example, an anti-anxiety drug or antidepressant selected from the group consisting of
- the other agent may be, for example, an anti-multiple sclerosis drug selected from the group consisting of
- compositions e.g. for parenteral, enteral or oral administration, comprising at least one QC inhibitor, optionally in combination with at least one of the other aforementioned agents.
- the invention provides a method for the treatment of these conditions.
- the method comprises either co-administration of at least one QC inhibitor and at least one of the other agents or the sequential administration thereof.
- Co-administration includes administration of a formulation, which comprises at least one QC inhibitor and at least one of the other agents or the essentially simultaneous administration of separate formulations of each agent.
- Beta-amyloid antibodies and compositions containing the same are described, e.g. in WO 2006/137354, WO 2006/118959, WO 2006/103116, WO 2006/095041, WO 2006/081171, WO 2006/066233, WO 2006/066171, WO 2006/066089, WO 2006/066049, WO 2006/055178, WO 2006/046644, WO 2006/039470, WO 2006/036291, WO 2006/026408, WO 2006/016644, WO 2006/014638, WO 2006/014478, WO 2006/008661, WO 2005/123775, WO 2005/120571, WO 2005/105998, WO 2005/081872, WO 2005/080435, WO 2005/028511, WO 2005/025616, WO 2005/025516, WO 2005/023858, WO 2005/018424, WO 2005/011599, WO 2005/000193, WO 2004/10
- the beta-amyloid antibodies may be selected from, for example, polyclonal, monoclonal, chimenic or humanized antibodies. Furthermore, said antibodies may be useful to develop active and passive immune therapies, i.e. vaccines and monoclonal antibodies.
- Suitable examples of beta-amyloid antibodies are ACU-5A5, huC091 (Acumen/Merck); PF-4360365, RI-1014, RI-1219, RI-409, RN-1219 (Rinat Neuroscience Corp (Pfizer Inc)); the nanobody therapeutics of Ablynx/Boehringer Ingelheim; beta-amyloid-specific humanized monoclonal antibodies of Intellect Neurosciences/IBL; m266, m266.2 (Eli Lilly & Co.); AAB-02 (Elan); bapineuzumab (Elan); BAN-2401 (Bioarctic Neuroscience AB); ABP-102 (Abiogen Pharma SpA); BA-27, BC-05 (Takeda); R-1450
- antibodies which recognize the N-terminus of the A ⁇ peptide.
- a suitable antibody, which recognizes the A ⁇ -N-Terminus is, for example Acl-24 (AC Immune SA).
- a monoclonal antibody against beta-amyloid peptide is disclosed in WO 2007/068412. Respective chimeric and humanized antibodies are disclosed in WO 2008/011348.
- a method for producing a vaccine composition for treating an amyloid-associated disease is disclosed in WO 2007/068411.
- Suitable cysteine protease inhibitors are inhibitors of cathepsin B.
- Inhibitors of cathepsin B and compositions containing such inhibitors are described, e.g. in WO 2006/060473, WO 2006/042103, WO 2006/039807, WO 2006/021413, WO 2006/021409, WO 2005/097103, WO 2005/007199, WO2004/084830, WO 2004/078908, WO 2004/026851, WO 2002/094881, WO 2002/027418, WO 2002/021509, WO 1998/046559, WO 1996/021655.
- PIMT enhancers are 10-aminoaliphatyl-dibenz[b,f]oxepines described in WO 98/15647 and WO 03/057204, respectively. Further useful according to the present invention are modulators of PIMT activity described in WO 2004/039773.
- Inhibitors of beta secretase and compositions containing such inhibitors are described, e.g. in WO03/059346, WO2006/099352, WO2006/078576, WO2006/060109, WO2006/057983, WO2006/057945, WO2006/055434, WO2006/044497, WO2006/034296, WO2006/034277, WO2006/029850, WO2006/026204, WO2006/014944, WO2006/014762, WO2006/002004, U.S. Pat. No.
- beta secretase inhibitors for the purpose of the present invention are WY-25105 (Wyeth); Posiphen, (+)-phenserine (TorreyPines/NIH); LSN-2434074, LY-2070275, LY-2070273, LY-2070102 (Eli Lilly & Co.); PNU-159775A, PNU-178025A, PNU-17820A, PNU-33312, PNU-38773, PNU-90530 (Elan/Pfizer); KMI-370, KMI-358, kmi-008 (Kyoto University); OM-99-2, OM-003 (Athenagen Inc.); AZ-12304146 (AstraZeneca/Astex); GW-840736X (GlaxoSmithKline plc.), DNP-004089 (De Novo Pharmaceuticals Ltd.) and CT-21166 (CoMentis Inc.).
- Inhibitors of gamma secretase and compositions containing such inhibitors are described, e.g. in WO2005/008250, WO2006/004880, U.S. Pat. Nos. 7,122,675, 7,030,239, 6,992,081, 6,982,264, WO2005/097768, WO2005/028440, WO2004/101562, U.S. Pat. Nos. 6,756,511, 6,683,091, WO03/066592, WO03/014075, WO03/013527, WO02/36555, WO01/53255, U.S. Pat. Nos.
- Suitable gamma secretase inhibitors for the purpose of the present invention are GSI-953, WAY-GSI-A, WAY-GSI-B (Wyeth); MK-0752, MRK-560, L-852505, L-685-458, L-852631, L-852646 (Merck & Co. Inc.); LY-450139, LY-411575, AN-37124 (Eli Lilly & Co.); BMS-299897, BMS-433796 (Bristol-Myers Squibb Co.); E-2012 (Eisai Co. Ltd.); EHT-0206, EHT-206 (ExonHit Therapeutics SA); and NGX-555 (TorreyPines Therapeutics Inc.).
- DP IV-inhibitors and compositions containing such inhibitors are described, e.g. in U.S. Pat. Nos. 6,011,155; 6,107,317; 6,110,949; 6,124,305; 6,172,081; WO99/61431, WO99/67278, WO99/67279, DE19834591, WO97/40832, WO95/15309, WO98/19998, WO00/07617, WO99/38501, WO99/46272, WO99/38501, WO01/68603, WO01/40180, WO01/81337, WO01/81304, WO01/55105, WO02/02560, WO01/34594, WO02/38541, WO02/083128, WO03/072556, WO03/002593, WO03/000250, WO03/000180, WO03/000181, EP1258476, WO03/002553, WO03/
- Suitable DP IV-inhibitors for the purpose of the present invention are for example Sitagliptin, des-fluoro-sitagliptin (Merck & Co. Inc.); vildagliptin, DPP-728, SDZ-272-070 (Novartis); ABT-279, ABT-341 (Abbott Laboratories); denagliptin, TA-6666 (GlaxoSmithKline plc.); SYR-322 (Takeda San Diego Inc.); talabostat (Point Therapeutics Inc.); Ro-0730699, R-1499, R-1438 (Roche Holding AG); FE-999011 (Ferring Pharmaceuticals); TS-021 (Taisho Pharmaceutical Co.
- GRC-8200 (Glenmark Pharmaceuticals Ltd.); ALS-2-0426 (Alantos Pharmaceuticals Holding Inc.); ARI-2243 (Arisaph Pharmaceuticals Inc.); SSR-162369 (Sanofi-Synthelabo); MP-513 (Mitsubishi Pharma Corp.); DP-893, CP-867534-01 (Pfizer Inc.); TSL-225, TMC-2A (Tanabe Seiyaku Co.
- PHX-1149 Phenomenix Corp.
- saxagliptin Bristol-Myers Squibb Co.
- PSN-9301 ((OSI) Prosidion), S-40755 (Servier)
- KRP-104 ActivX Biosciences Inc.
- sulphostin Zaidan Hojin
- KR-62436 Korea Research Institute of Chemical Technology
- P32/98 Probiodrug AG
- BI-A, BI-B Boehringer Ingelheim Corp.
- SK-0403 Sawa Kagaku Kenkyusho Co. Ltd.
- NNC-72-2138 Novo Nordisk NS
- Suitable beta amyloid synthesis inhibitors for the purpose of the present invention are for example Bisnorcymserine (Axonyx Inc.); (R)-flurbiprofen (MCP-7869; Flurizan) (Myriad Genetics); nitroflurbiprofen (NicOx); BGC-20-0406 (Sankyo Co. Ltd.) and BGC-20-0466 (BTG plc.).
- Suitable amyloid protein deposition inhibitors for the purpose of the present invention are for example SP-233 (Samaritan Pharmaceuticals); AZD-103 (Ellipsis Neurotherapeutics Inc.); AAB-001 (Bapineuzumab), AAB-002, ACC-001 (Elan Corp plc.); Colostrinin (ReGen Therapeutics plc.); Tramiprosate (Neurochem); AdPEDI-(amyloid-beta1-6)11) (Vaxin Inc.); MPI-127585, MPI-423948 (Mayo Foundation); SP-08 (Georgetown University); ACU-5A5 (Acumen/Merck); Transthyretin (State University of New York); PTI-777, DP-74, DP 68, Exebryl (ProteoTech Inc.); m266 (Eli Lilly & Co.); EGb-761 (Dr.
- Suitable PDE-4 inhibitors for the purpose of the present invention are for example Doxofylline (Instituto Biologico Chemioterapica ABC SpA.); idudilast eye drops, tipelukast, ibudilast (Kyorin Pharmaceutical Co.
- a preferred PDE-4-inhibitor is Rolipram.
- MAO inhibitors and compositions containing such inhibitors are described, e.g. in WO2006/091988, WO2005/007614, WO2004/089351, WO01/26656, WO01/12176, WO99/57120, WO99/57119, WO99/13878, WO98/40102, WO98/01157, WO96/20946, WO94/07890 and WO92/21333.
- Suitable MAO-inhibitors for the purpose of the present invention are for example Linezolid (Pharmacia Corp.); RWJ-416457 (RW Johnson Pharmaceutical Research Institute); budipine (Altana AG); GPX-325 (BioResearch Ireland); isocarboxazid; phenelzine; tranylcypromine; indantadol (Chiesi Farmaceutici SpA.); moclobemide (Roche Holding AG); SL-25.1131 (Sanofi-Synthelabo); CX-1370 (Burroughs Wellcome Co.); CX-157 (Krenitsky Pharmaceuticals Inc.); desoxypeganine (HF Arzneiffenforschung GmbH & Co.
- Linezolid Pharmacia Corp.
- RWJ-416457 RW Johnson Pharmaceutical Research Institute
- budipine Altana AG
- GPX-325 BioResearch Ireland
- isocarboxazid phenelzine
- Suitable histamine H3 antagonists for the purpose of the present invention are, e.g. ABT-239, ABT-834 (Abbott Laboratories); 3874-H1 (Aventis Pharma); UCL-2173 (Berlin Free University), UCL-1470 (BioProjet, Societe Civile de für); DWP-302 (Daewoong Pharmaceutical Co Ltd); GSK-189254A, GSK-207040A (GlaxoSmithKline Inc.); cipralisant, GT-2203 (Gliatech Inc.); Ciproxifan (INSERM), 1S,2S-2-(2-Aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (Hokkaido University); JNJ-17216498, JNJ-5207852 (Johnson & Johnson); NNC-0038-0000-1049 (Novo Nordisk NS); and Sch-79687 (Schering-Plough).
- ABT-239, ABT-834
- PEP inhibitors and compositions containing such inhibitors are described, e.g. in JP 01042465, JP 03031298, JP 04208299, WO 00/71144, U.S. Pat. No. 5,847,155; JP 09040693, JP 10077300, JP 05331072, JP 05015314, WO 95/15310, WO 93/00361, EP 0556482, JP 06234693, JP 01068396, EP 0709373, U.S. Pat. Nos.
- Suitable prolyl endopeptidase inhibitors for the purpose of the present invention are, e.g. Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-Benzothiazole (Probiodrug), Z-321 (Zeria Pharmaceutical Co Ltd.); ONO-1603 (Ono Pharmaceutical Co Ltd); JTP-4819 (Japan Tobacco Inc.) and S-17092 (Servier).
- NPY neuropeptide Y
- NPY mimetic NPY mimetic
- NPY agonist or antagonist NPY ligand of the NPY receptors.
- Preferred according to the present invention are antagonists of the NPY receptors.
- Suitable ligands or antagonists of the NPY receptors are 3a,4,5,9b-tetrahydro-1h-benz[e]indol-2-yl amine-derived compounds as disclosed in WO 00/68197.
- NPY receptor antagonists which may be mentioned include those disclosed in European patent applications EP 0 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; WO 00/30674, U.S.
- NPY antagonists include those compounds that are specifically disclosed in these patent documents. More preferred compounds include amino acid and non-peptide-based NPY antagonists.
- Amino acid and non-peptide-based NPY antagonists which may be mentioned include those disclosed in European patent applications EP 0 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO 99/15498; U.S. Pat. Nos. 5,552,411, 5,663,192 and
- Particularly preferred compounds include amino acid-based NPY antagonists.
- Amino acid-based compounds which may be mentioned include those disclosed in international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 97/19914 or, preferably, WO 99/15498.
- Preferred amino acid-based NPY antagonists include those that are specifically disclosed in these patent documents, for example BIBP3226 and, especially, (R)—N-2-(diphenylacetyl)-(R)—N-[1-(4-hydroxy-phenyl)ethyl]arginine amide (Example 4 of international patent application WO 99/15498).
- M1 receptor agonists and compositions containing such inhibitors are described, e.g. in WO2004/087158, WO91/10664.
- Suitable M1 receptor antagonists for the purpose of the present invention are for example CDD-0102 (Cognitive Pharmaceuticals); Cevimeline (Evoxac) (Snow Brand Milk Products Co. Ltd.); NGX-267 (TorreyPines Therapeutics); sabcomeline (GlaxoSmithKline); alvameline (H Lundbeck NS); LY-593093 (Eli Lilly & Co.); VRTX-3 (Vertex Pharmaceuticals Inc.); WAY-132983 (Wyeth) and CI-101 7/(PD-151832) (Pfizer Inc.).
- Acetylcholinesterase inhibitors and compositions containing such inhibitors are described, e.g. in WO2006/071274, WO2006/070394, WO2006/040688, WO2005/092009, WO2005/079789, WO2005/039580, WO2005/027975, WO2004/084884, WO2004/037234, WO2004/032929, WO03/101458, WO03/091220, WO03/082820, WO03/020289, WO02/32412, WO01/85145, WO01/78728, WO01/66096, WO00/02549, WO01/00215, WO00/15205, WO00/23057, WO00/33840, WO00/30446, WO00/23057, WO00/15205, WO00/09483, WO00/07600, WO00/02549, WO99/47131, WO99/07359
- Suitable acetylcholinesterase inhibitors for the purpose of the present invention are for example Donepezil (Eisai Co. Ltd.); rivastigmine (Novartis AG); ( ⁇ )-phenserine (TorreyPines Therapeutics); ladostigil (Hebrew University of Jerusalem); huperzine A (Mayo Foundation); galantamine (Johnson & Johnson); Memoquin (Universita di Bologna); SP-004 (Samaritan Pharmaceuticals Inc.); BGC-20-1259 (Sankyo Co.
- NMDA receptor antagonists and compositions containing such inhibitors are described, e.g. in WO2006/094674, WO2006/058236, WO2006/058059, WO2006/010965, WO2005/000216, WO2005/102390, WO2005/079779, WO2005/079756, WO2005/072705, WO2005/070429, WO2005/055996, WO2005/035522, WO2005/009421, WO2005/000216, WO2004/092189, WO2004/039371, WO2004/028522, WO2004/009062, WO03/010159, WO02/072542, WO02/34718, WO01/98262, WO01/94321, WO01/92204, WO01/81295, WO01/32640, WO01/10833, WO01/10831, WO00/56711, WO00/29023, WO00/00
- Suitable NMDA receptor antagonists for the purpose of the present invention are for example Memantine (Merz & Co. GmbH); topiramate (Johnson & Johnson); AVP-923 (Neurodex) (Center for Neurologic Study); EN-3231 (Endo Pharmaceuticals Holdings Inc.); neramexane (MRZ-2/579) (Merz and Forest); CNS-5161 (CeNeS Pharmaceuticals Inc.); dexanabinol (HU-211; Sinnabidol; PA-50211) (Pharmos); EpiCept NP-1 (Dalhousie University); indantadol (V-3381; CNP-3381) (Vernalis); perzinfotel (EAA-090, WAY-126090, EAA-129) (Wyeth); RGH-896 (Gedeon Richter Ltd.); traxoprodil (CP-101606), besonprodil (PD-196860, CI-1041) (Pfizer Inc.); CGX-10
- the present invention relates to combination therapies useful for the treatment of atherosclerosis, restenosis or arthritis, administering a QC inhibitor in combination with another therapeutic agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-1 antagonists and tyrosine kinase inhibitors providing beneficial or synergistic therapeutic effects over each monotherapy component alone.
- ACE angiotensin converting enzyme
- CB calcium channel blockers
- beta-blockers beta-blockers
- Angiotensin II receptor blockers are understood to be those active agents that bind to the AT1-receptor subtype of angiotensin II receptor but do not result in activation of the receptor. As a consequence of the blockade of the AT1 receptor, these antagonists can, e.g. be employed as antihypertensive agents.
- Suitable angiotensin II receptor blockers which may be employed in the combination of the present invention include AT, receptor antagonists having differing structural features, preferred are those with non-peptidic structures.
- AT receptor antagonists having differing structural features
- non-peptidic structures For example, mention may be made of the compounds that are selected from the group consisting of valsartan (EP 443983), losartan (EP 253310), candesartan (EP 459136), eprosartan (EP 403159), irbesartan (EP 454511), olmesartan (EP 503785), tasosartan (EP 539086), telmisartan (EP 522314), the compound with the designation E-41 77 of the formula
- Preferred AT1-receptor antagonists are those agents that have been approved and reached the market, most preferred is valsartan, or a pharmaceutically acceptable salt thereof.
- the interruption of the enzymatic degradation of angiotensin to angiotensin II with ACE inhibitors is a successful variant for the regulation of blood pressure and thus also makes available a therapeutic method for the treatment of hypertension.
- a suitable ACE inhibitor to be employed in the combination of the present invention is, e.g. a compound selected from the group consisting alacepril, benazepril, benazeprilat; captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril and trandolapril, or in each case, a pharmaceutically acceptable salt thereof.
- Preferred ACE inhibitors are those agents that have been marketed, most preferred are benazepril and enalapril.
- a diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon.
- the most preferred diuretic is hydrochlorothiazide.
- a diuretic furthermore comprises a potassium sparing diuretic such as amiloride or triameterine, or a pharmaceutically acceptable salt thereof.
- the class of CCBs essentially comprises dihydropyridines (DHPs) and non-DHPs, such as diltiazem-type and verapamil-type CCBs.
- DHPs dihydropyridines
- non-DHPs such as diltiazem-type and verapamil-type CCBs.
- a CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in each case, a pharmaceutically acceptable salt thereof. All these CCBs are therapeutically used, e.g. as anti-hypertensive, anti-angina pectoris or anti-arrhythmic drugs.
- Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof.
- DHP is amlodipine or a pharmaceutically acceptable salt thereof, especially the besylate.
- An especially preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof.
- Beta-blockers suitable for use in the present invention include beta-adrenergic blocking agents (beta-blockers), which compete with epinephrine for beta-adrenergic receptors and interfere with the action of epinephrine.
- beta-blockers are selective for the beta-adrenergic receptor as compared to the alpha-adrenergic receptors, and so do not have a significant alpha-blocking effect.
- Suitable beta-blockers include compounds selected from acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol.
- beta-blocker is an acid or base or otherwise capable of forming pharmaceutically acceptable salts or prodrugs
- these forms are considered to be encompassed herein, and it is understood that the compounds may be administered in free form or in the form of a pharmaceutically acceptable salt or a prodrug, such as a physiologically hydrolyzable and acceptable ester.
- a pharmaceutically acceptable salt or a prodrug such as a physiologically hydrolyzable and acceptable ester.
- metoprolol is suitably administered as its tartrate salt
- propranolol is suitably administered as the hydrochloride salt, and so forth.
- Platelet aggregation inhibitors include PLAVIX® (clopidogrel bisulfate), PLETAL® (cilostazol) and aspirin.
- Cholesterol absorption modulators include ZETIA® (ezetimibe) and KT6-971 (Kotobuki Pharmaceutical Co. Japan).
- HMG-Co-A reductase inhibitors also called beta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors or statins
- statins are understood to be those active agents which may be used to lower lipid levels including cholesterol in blood.
- the class of HMG-Co-A reductase inhibitors comprises compounds having differing structural features.
- the compounds which are selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or in each case, a pharmaceutically acceptable salt thereof.
- HMG-Co-A reductase inhibitors are those agents, which have been marketed, most preferred is atorvastatin, pitavastatin or simvastatin, or a pharmaceutically acceptable salt thereof.
- HDL-increasing compounds include, but are not limited to, cholesterol ester transfer protein (CETP) inhibitors.
- CETP inhibitors include JTT7O5 disclosed in Example 26 of U.S. Pat. No. 6,426,365 issued Jul. 30, 2002, and pharmaceutically acceptable salts thereof.
- Interleukin 6 mediated inflammation may be achieved indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion or by direct inhibition of the signal transduction pathway utilizing interleukin-6 inhibitor/antibody, interleukin-6 receptor inhibitor/antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor/antibody, tyrosine kinase inhibitors/antibodies, serine/threonine kinase inhibitors/antibodies, mitogen-activated protein (MAP) kinase inhibitors/antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, Nuclear factor kappaB (NF-KB) inhibitors/antibodies, IKB kinase (IKK) inhibitors/antibodies, activator protein-1 (AP-1) inhibitors/antibodies, STAT transcription factors inhibitors/antibodies, altered IL-6, partial peptides
- a suitable antiinflammatory corticosteroid is dexamethasone.
- Suitable antiproliferative agents are cladribine, rapamycin, vincristine and taxol.
- a suitable inhibitor of extracellular matrix synthesis is halofuginone.
- a suitable growth factor or cytokine signal transduction inhibitor is, e.g. the ras inhibitor R115777.
- a suitable tyrosine kinase inhibitor is tyrphostin.
- Suitable renin inhibitors are described, e.g. in WO 2006/116435.
- a preferred renin inhibitor is aliskiren, preferably in the form of the hemi-fumarate salt thereof.
- MCP-1 antagonists may, e.g. be selected from anti-MCP-1 antibodies, preferably monoclonal or humanized monoclonal antibodies, MCP-1 expression inhibitors, CCR2-antagonists, TNF-alpha inhibitors, VCAM-1 gene expression inhibitors and anti-05a monoclonal antibodies.
- MCP-1 antagonists and compositions containing such inhibitors are described, e.g. in WO02/070509, WO02/081463, WO02/060900, US2006/670364, US2006/677365, WO2006/097624, US2006/316449, WO2004/056727, WO03/053368, WO00/198289, WO00/157226, WO00/046195, WO00/046196, WO00/046199, WO00/046198, WO00/046197, WO99/046991, WO99/007351, WO98/006703, WO97/012615, WO2005/105133, WO03/037376, WO2006/125202, WO2006/085961, WO2004/024921, WO2006/074265.
- Suitable MCP-1 antagonists are, for instance, C-243 (Telik Inc.); NOX-E36 (Noxxon Pharma AG); AP-761 (Actimis Pharmaceuticals Inc.); ABN-912, NIBR-177 (Novartis AG); CC-11006 (Celgene Corp.); SSR-150106 (Sanofi-Aventis); MLN-1202 (Millenium Pharmaceuticals Inc.); AG1-1067, AGIX-4207, AGM 096 (AtherioGenics Inc.); PRS-211095, PRS-211092 (Pharmos Corp.); anti-05a monoclonal antibodies, e.g.
- neutrazumab G2 Therapies Ltd.
- AZD-6942 AstraZeneca plc.
- 2-mercaptoimidazoles Johnson & Johnson
- TEI-E00526, TEI-6122 Deltagen
- RS-504393 Roche Holding AG
- SB-282241, SB-380732, ADR-7 GaxoSmithKline
- anti-MCP-1 monoclonal antibodies Johnson & Johnson.
- Combinations of QC-inhibitors with MCP-1 antagonists may be useful for the treatment of inflammatory diseases in general, including neurodegenerative diseases.
- Combinations of QC-inhibitors with MCP-1 antagonists are preferred for the treatment of Alzheimer's disease.
- the QC inhibitor is combined with one or more compounds selected from the following group:
- PF-4360365 m266, bapineuzumab, R-1450, Posiphen, (+)-phenserine, MK-0752, LY-450139, E-2012, (R)-flurbiprofen, AZD-103, AAB-001 (Bapineuzumab), Tramiprosate, EGb-761, TAK-070, Doxofylline, theophylline, cilomilast, tofimilast, roflumilast, tetomilast, tipelukast, ibudilast, HT-0712, MEM-1414, oglemilast, Linezolid, budipine, isocarboxazid, phenelzine, tranylcypromine, indantadol, moclobemide, rasagiline, ladostigil, safinamide, ABT-239, ABT-834, GSK-189254A, Ciproxifan
- Such a combination therapy is in particular useful for AD, FAD, FDD and neurodegeneration in Down syndrome as well as atherosclerosis, rheumatoid arthritis, restenosis and pancreatitis.
- Such combination therapies might result in a better therapeutic effect (less proliferation as well as less inflammation, a stimulus for proliferation) than would occur with either agent alone.
- At least one compound of formula (I) optionally in combination with at least one of the other aforementioned agents can be used as the active ingredient(s).
- the active ingredient(s) is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
- a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
- any of the usual pharmaceutical media may be employed.
- suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
- suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
- tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
- the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
- Injectable suspensions may also prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
- the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient(s) necessary to deliver an effective dose as described above.
- the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, from about 0.03 mg to 100 mg/kg (preferred 0.1-30 mg/kg) and may be given at a dosage of from about 0.1-300 mg/kg per day (preferred 1-50 mg/kg per day) of each active ingredient or combination thereof.
- the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
- compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
- the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
- a pharmaceutical carrier e.g.
- a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
- This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of each active ingredient or combinations thereof of the present invention.
- the tablets or pills of the compositions of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
- the pharmaceutical composition may contain between about 0.01 mg and 100 mg, preferably about 5 to 50 mg, of each compound, and may be constituted into any form suitable for the mode of administration selected.
- Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
- Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
- Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
- compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
- compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- liquid forms in suitable flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
- suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
- tragacanth for example, tragacanth, acacia, methyl-cellulose and the like.
- methyl-cellulose methyl-cellulose and the like.
- suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
- sterile suspensions and solutions are desired.
- Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
- the compounds or combinations of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- Compounds or combinations of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamid-ephenol, or polyethyl eneoxidepolyllysine substituted with palmitoyl residue.
- the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- Compounds or combinations of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of the addressed disorders is required.
- the daily dosage of the products may be varied over a wide range from 0.01 to 1.000 mg per mammal per day.
- the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of each active ingredient or combinations thereof for the symptomatic adjustment of the dosage to the patient to be treated.
- An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 300 mg/kg of body weight per day.
- the range is from about 1 to about 50 mg/kg of body weight per day.
- the compounds or combinations may be administered on a regimen of 1 to 4 times per day.
- Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
- the invention also provides a process for preparing a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of formula (I), optionally in combination with at least one of the other aforementioned agents and a pharmaceutically acceptable carrier.
- compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
- Suitable dosages, including especially unit dosages, of the compounds of the present invention include the known dosages including unit doses for these compounds as described or referred to in reference text such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) or the above mentioned publications.
- numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the present disclosure are to be understood as being modified in some instances by the term “about.”
- the term “about” is used to indicate that a value includes the standard deviation of the mean for the device or method being employed to determine the value.
- the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment.
- the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
- the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural, unless specifically noted otherwise.
- the term “or” as used herein, including the claims, is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive.
- Benzimidazol-5-amine (1 eq.) was suspended in dry toluol (50 ml). After addition of the respective aldehyde (1.1 eq.), the mixture was heated to reflux for 3 h. The solvent was removed in vacuo and the remains were dissolved in dry EtOH (100 ml). This solution was added dropwise to a solution of NaBH 4 (1.5 eq.) in EtOH (50 ml) at room temperature. After stirring for 1 h the mixture was heated to reflux for an additional 4 h. After the addition of 5 N NaOH (5 eq.) the reaction was stirred at 60° C. overnight. The solvent was concentrated by half, diluted with water and extracted by means of ethyl acetate (3 ⁇ 100 ml). The combined organic layers were dried over Na 2 SO 4 , evaporated and the residue was purified by flash chromatography on silica using a CHCl 3 /MeOH gradient.
- Benzimidazol-5-amine (1 eq.) was dissolved in MeOH (10 ml) and treated with the respective aldehyde or ketone (1.1 eq.). After the addition of molsieves 3 ⁇ the mixture was stirred at room temperature for 24 h. NaBH 4 (2 eq.) was added and the mixture was stirred for 1 h and heated to reflux for additional 4 h. After the addition of 5 N NaOH (5 eq.) the mixture was stirred at 60° C. overnight. The mixture was diluted with water and extracted by means of ethyl acetate (3 ⁇ 25 ml). The combined organic layers were dried over Na 2 SO 4 , evaporated and the residue was purified by flash chromatography on silica using a CHCl 3 /MeOH gradient.
- N1-Boc-benzimidazol-5-amine (1 eq.) was dissolved in DMF (5 ml) and treated with K 2 CO 3 (2.5 eq.) and the respective benzylhalide (2.5 eq.). After stirring at room temperature for 24 h the mixture was diluted with water and extracted by means of ethyl acetate (3 ⁇ 25 ml). The combined organic layers were dried over Na 2 SO 4 and the solvent was removed in vacuo. The residue was redissolved in THF (5 ml), treated with 5 N NaOCH 3 (3 eq.) and stirred at room temperature for 1 h. The mixture was diluted with water and extracted by means of ethyl acetate (3 ⁇ 25 ml). The combined organic layers were dried over Na 2 SO 4 , evaporated and the residue was purified by flash chromatography on silica using a CHCl 3 /MeOH gradient.
- Benzimidazol-5-carbaldehyde (1 eq.) was dissolved in THF (10 ml). The respective amine (1 eq.), NaBH(AcO) 3 (1.5 eq.) and AcOH (1.5 eq.) were added and the mixture was stirred at room temperature overnight. The mixture was basified by means of 1 M aqueous NaOH and extracted with ethyl acetate (3 ⁇ 25 ml). The combined organic layers were dried over Na 2 SO 4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl 3 /MeOH gradient.
- the compound was synthesized starting from 5-bromobenzimidazole (1.0 g; 5 mmol; 1 eq.), aniline (559 mg; 0.547 ml; 6 mmol; 1.2 eq.), lithiumbis(trimethylsilyl)amide 1M in THF (11 ml; 11 mmol; 2.2 eq.), 2-dicyclohexylphos-phino-2′′-(N,N-dimethylamino)biphenyl) (45 mg; 0.12 mmol; 0.024 eq.; 2.4 mol %), Pd 2 dba 3 (45 mg; 0.05 mmol; 0.01 eq.; 1 mol %) and THF (5 ml) according to method 1; Yield: 0.565 g (54.1%); MS m/z: 210.2 [M+H] + ; 1 H-NMR (500 MHz, DMSO d6): ⁇ 6.72-6.75 (m, 1H); 6.94
- Benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.) was dissolved in MeOH (10 ml). Benzylamine (0.109 ml; 1 mmol; 1 eq.) was added and the mixture was stirred overnight. NaBH 4 (57 mg; 1.5 mmol; 1.5 eq.) was added and stirring was continued overnight. The reaction was quenched by addition of water and extracted with ethyl acetate (3 ⁇ 25 ml). The combined organic layers were dried over Na 2 SO 4 and evaporated. The residue was purified by flashchromatography on silica using a CHCl 3 /MeOH gradient.
- the compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 4-methoxybenzylamine (165 mg; 0.156 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd 2 dba 3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.058 g (22.9%); MS m/z: 254.3 [M+H] + ; 1 H-NMR (500 MHz, DMSO d6): ⁇ 3.69 (s, 3H); 4.19 (d, 2H, 3
- the compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 3,4-dimethoxybenzylamine (201 mg; 0.181 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd 2 dba 3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.064 g (22.6%); MS m/z: 284.1 [M+H] + ; 1 H-NMR (500 MHz, DMSO d6): ⁇ 3.69 (s, 3H); 3.71 (s,
- the compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 4-methylbenzylamine (145 mg; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd 2 dba 3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.058 g (24.5%); MS m/z: 238.3 [M+H] + ; 1 H-NMR (500 MHz, DMSO d6): ⁇ 2.24 (s, 3H); 4.21 (s, 2H); 5.97 (br s
- the compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 4-fluorobenzylamine (150 mg; 0.137 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd 2 dba 3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.096 mg (39.8%); MS m/z: 242.4 [M+H] + ; 1 H-NMR (500 MHz, DMSO d6): ⁇ 4.25 (s, 2H); 6.04 (br s, 1H
- the compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), dibenzylamine (0.231 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd 2 dba 3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1 but purified by flash chromatography on silica using a CHCl 3 /MeOH gradient; Yield: 0.127 g (41%); 314.1 MS m/z: [M+H] + ; 1 H-NMR (500 MHz, DMSO d6): ⁇ 4.
- the compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-methylthiobenzaldehyde (3.35 g; 2.9 ml; 22 mmol; 1.1 eq.), NaBH 4 (1.14 g; 30 mmol; 1.5 eq.) and 5 N NaOH (20 ml; 100 mmol; 5 eq.) according to method 2; Yield: 3.79 g (70.5%); MS m/z: 270.5 [M+H] +
- the compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 2,5-dichlorobenzylbromide (528 mg; 2.2 mmol; 2.2 eq.) and K 2 CO 3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5.
- the compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 2,3,5,6-tetrafluoro-4-methylbenzylbromide (566 mg; 2.2 mmol; 2.2 eq.) and K 2 CO 3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5.
- N 1 -Boc-N-(4-methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K 2 CO 3 (166 mg; 1.2 mmol; 1.2 eq.) and benzylbromide (0.143 ml; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h.
- the mixture was diluted with water and extracted with ethyl acetate (3 ⁇ 25 ml).
- the combined organic layers were dried over Na 2 SO 4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH 3 and stirred for 2 h at room temperature.
- N 1 -Boc-N-(4-methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K 2 CO 3 (166 mg; 1.2 mmol; 1.2 eq.) and naphthalen-2-yl-methyl-bromide (265 mg; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3 ⁇ 25 ml). The combined organic layers were dried over Na 2 SO 4 and evaporated.
- N 1 -Trityl-N-(4-methoxyphenyl)benzimidazol-5-amine (990 mg; 2 mmol; 1 eq.) was dissolved in THF (5 ml), cooled to 0° C. and treated with lithiumbis(trimethylsilyl)amide 1M in THF (2.4 ml; 2.4 mmol; 1.2 eq.).
- Phenylethylbromide (0.330 ml; 2.4 mmol; 2.4 eq.) was added and the mixture was stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3 ⁇ 25 ml). The combined organic layers were dried over Na 2 SO 4 and evaporated.
- N 1 -Boc-N-(4-Methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K 2 CO 3 (166 mg; 1.2 mmol; 1.2 eq.) and phenylpropylbromide (0.183 ml; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h.
- the mixture was diluted with water and extracted with ethyl acetate (3 ⁇ 25 ml).
- the combined organic layers were dried over Na 2 SO 4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH 3 and stirred for 2 h at room temperature.
- N 1 -Trityl-N-phenyl-benzimidazol-5-amine (1.13 g; 2.5 mmol; 1 eq.) was dissolved in THF (5 ml), cooled to 0° C. and treated with lithiumbis(trimethylsilyl)amide 1M in THF (3 ml; 3 mmol; 1.2 eq.).
- Benzylbromide (3 mmol; 1.2 eq.) was added and stirred at room temperature for 24 h.
- the mixture was diluted with water and extracted with ethyl acetate (3 ⁇ 25 ml).
- the combined organic layers were dried over Na 2 SO 4 and evaporated.
- the residue was dissolved in MeOH (5 ml) and treated with TFA (1 ml).
- the compound was synthesized starting from benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), aniline (0.095 ml; 1 mmol; 1 eq.), NaBH(AcO) 3 (318 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml; 1.5 mmol; 1.5 eq.) as described above.
- the compound was synthesized starting from benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), phenylethylamine (0.126 ml; 1 mmol; 1 eq.); NaBH(AcO) 3 (318 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml; 1.5 mmol; 1.5 eq.) as described above.
- the compound was synthesized starting from benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), 4-methoxy-N-methylaniline (137 mg g; 1 mmol; 1 eq.); NaBH(AcO) 3 (318 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml; 1.5 mmol; 1.5 eq.) as described above.
- the compound was synthesized starting from benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), 4-fluoro-N-methylaniline (0.147 ml; 1 mmol; 1 eq.); NaBH(AcO) 3 (318 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml; 1.5 mmol; 1.5 eq.) as described above.
- the compounds were analyzed using a gradient at a flow rate of 1 mL/min; whereby eluent (A) was acetonitrile. eluent (B) was water. both containing 0.1% (v/v) trifluoro acetic acid applying the following gradient: Method [A]:0 min-5 min.
- QC activity was determined from a standard curve of /3-naphthylamine under assay conditions. One unit is defined as the amount of QC catalyzing the formation of 1 ⁇ mol pGlu- ⁇ NA from H-Gln-/3NA per minute under the described conditions.
- QC was activity determined using H-Gln-AMC as substrate. Reactions were carried out at 30° C. utilizing the NOVOStar reader for microplates (BMG labtechnologies). The samples consisted of varying concentrations of the fluorogenic substrate, 0.1 U pyroglutamyl aminopeptidase (Qiagen) in 0.05 M Tris/HCl, pH 8.0 containing 5 mM EDTA and an appropriately diluted aliquot of QC in a final volume of 250 ⁇ l. Excitation/emission wavelengths were 380/460 nm. The assay reactions were initiated by addition of glutaminyl cyclase. QC activity was determined from a standard curve of 7-amino-4-methylcoumarin under assay conditions. The kinetic data were evaluated using GraFit software.
- This novel assay was used to determine the kinetic parameters for most of the QC substrates.
- QC activity was analyzed spectrophotometrically using a continuous method, that was derived by adapting a previous discontinuous assay (Bateman, R. C. J. 1989 J Neurosci Methods 30, 23-28) utilizing glutamate dehydrogenase as auxiliary enzyme.
- Samples consisted of the respective QC substrate, 0.3 mM NADH, 14 mM a-Ketoglutaric acid and 30 U/ml glutamate dehydrogenase in a final volume of 250 ⁇ l. Reactions were started by addition of QC and persued by monitoring of the decrease in absorbance at 340 nm for 8-15 min.
- the initial velocities were evaluated and the enzymatic activity was determined from a standard curve of ammonia under assay conditions. All samples were measured at 30° C., using either the SPECTRAFIuor Plus or the Sunrise (both from TECAN) reader for microplates. Kinetic data was evaluated using GraFit software.
- the sample composition was the same as described above, except for the putative inhibitory compound added.
- samples contained 4 mM of the respective inhibitor and a substrate concentration at 1 K M .
- influence of the inhibitor on the auxiliary enzymes was investigated first. In every case, there was no influence on either enzyme detected, thus enabling the reliable determination of the QC inhibition.
- the inhibitory constant was evaluated by fitting the set of progress curves to the general equation for competitive inhibition using GraFit software.
- a Merck-Hitachi device model LaChrom®
- LUNA® RP 18 5 ⁇ m
- analytical column length: 125 mm, diameter: 4 mm
- DAD diode array detector
- the compounds were analyzed using a gradient at a flow rate of 1 mL/min; whereby eluent (A) was acetonitrile, eluent (B) was water, both containing 0.1% (v/v) trifluoro acetic acid applying the following gradient:: 0 min-5 min ⁇ 5% (A), 5 min-17 min ⁇ 5-15% (A), 15 min-27 min ⁇ 15-95% (A) 27 min-30 min ⁇ 95% (A), Method [B]: 0 min-15 min ⁇ 5-60% (A), 15 min-20 min ⁇ 60-95% (A), 20 min-23 min ⁇ 95% (A), Method [C]: 0 min-20 min ⁇ 5-60% (A), 20 min-25 min ⁇ 60-95% (A). 25 min-30 min ⁇ 95% (A).
- the compounds were analyzed using a gradient at a flow rate of 0.6 mL/min; whereby eluent (A) was acetonitrile, eluent (B) was water and eluent (C) 2% formic acid in acetonitrile applying the following gradient:
- Matrix-assisted laser desorption/ionization mass spectrometry was carried out using the Hewlett-Packard G2025 LD-TOF System with a linear time of flight analyzer.
- the instrument was equipped with a 337 nm nitrogen laser, a potential acceleration source (5 kV) and a 1.0 m flight tube.
- Detector operation was in the positive-ion mode and signals are recorded and filtered using LeCroy 9350M digital storage oscilloscope linked to a personal computer. Samples (5 ⁇ l) were mixed with equal volumes of the matrix solution.
- DHAP/DAHC For matrix solution DHAP/DAHC was used, prepared by solving 30 mg 2′,6′-dihydroxyacetophenone (Aldrich) and 44 mg diammonium hydrogen citrate (Fluka) in 1 ml acetonitrile/0.1% TFA in water (1/1, v/v). A small volume ( ⁇ 1 ⁇ l) of the matrix-analyte-mixture was transferred to a probe tip and immediately evaporated in a vacuum chamber (Hewlett-Packard G2024A sample prep accessory) to ensure rapid and homogeneous sample crystallization.
- Aldrich 2′,6′-dihydroxyacetophenone
- Fluka diammonium hydrogen citrate
- Glu 1 -cyclization For long-term testing of Glu 1 -cyclization, An-derived peptides were incubated in 100 ⁇ l 0.1 M sodium acetate buffer, pH 5.2 or 0.1 M Bis-Tris buffer, pH 6.5 at 30° C. Peptides were applied in 0.5 mM [A ⁇ (3-11)a] or 0.15 mM [A ⁇ (3-21)a] concentrations, and 0.2 U QC is added all 24 hours. In case of A ⁇ (3-21)a, the assays contained 1% DMSO. At different times, samples are removed from the assay tube, peptides extracted using ZipTips (Millipore) according to the manufacturer's recommendations, mixed with matrix solution (1:1 v/v) and subsequently the mass spectra recorded. Negative controls either contain no QC or heat deactivated enzyme. For the inhibitor studies the sample composition was the same as described above, with exception of the inhibitory compound added (5 mM or 2 mM of a test compound of the invention).
- Compounds and combinations of the invention may have the advantage that they are, for example, more potent, more selective, have fewer side-effects, have better formulation and stability properties, have better pharmacokinetic properties, be more bioavailable, be able to cross blood brain barrier and are more effective in the brain of mammals, are more compatible or effective in combination with other drugs or be more readily synthesized than other compounds of the prior art.
- the invention embraces all combinations of preferred and more preferred groups and embodiments of groups recited above.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Oncology (AREA)
- Reproductive Health (AREA)
- Psychiatry (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Pregnancy & Childbirth (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Psychology (AREA)
- Dermatology (AREA)
- Gynecology & Obstetrics (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/091,276 US8541596B2 (en) | 2010-04-21 | 2011-04-21 | Inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US32640110P | 2010-04-21 | 2010-04-21 | |
US13/091,276 US8541596B2 (en) | 2010-04-21 | 2011-04-21 | Inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
US20110262388A1 US20110262388A1 (en) | 2011-10-27 |
US8541596B2 true US8541596B2 (en) | 2013-09-24 |
Family
ID=44247842
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/091,276 Active US8541596B2 (en) | 2010-04-21 | 2011-04-21 | Inhibitors |
Country Status (4)
Country | Link |
---|---|
US (1) | US8541596B2 (fr) |
EP (1) | EP2560953B1 (fr) |
JP (1) | JP5945532B2 (fr) |
WO (1) | WO2011131748A2 (fr) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103992310B (zh) * | 2013-05-14 | 2016-07-06 | 中国医学科学院医药生物技术研究所 | 一组取代苯并杂环胺衍生物及其制备方法和作为impdh抑制剂的相关应用 |
JP2018501482A (ja) | 2014-12-19 | 2018-01-18 | プロビオドルグ エージー | pGlu−Abetaペプチドの検出のための新規の方法 |
GB201705263D0 (en) | 2017-03-31 | 2017-05-17 | Probiodrug Ag | Novel inhibitors |
DK3461819T3 (da) | 2017-09-29 | 2020-08-10 | Probiodrug Ag | Inhibitorer af glutaminylcyklase |
EP3521308B1 (fr) | 2018-01-31 | 2024-03-13 | Vivoryon Therapeutics N.V. | Anticorps humanisés et dé-immunisés |
EP4361131A1 (fr) * | 2021-06-21 | 2024-05-01 | Iregene Therapeutics Ltd | Activateur d'oct4 à sélectivité élevée |
CN115572256A (zh) * | 2021-06-21 | 2023-01-06 | 武汉睿健医药科技有限公司 | Oct4高选择性活化剂 |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6224244A (ja) | 1985-07-24 | 1987-02-02 | Konishiroku Photo Ind Co Ltd | ハロゲン化銀写真感光材料 |
JPS6255644A (ja) * | 1985-09-04 | 1987-03-11 | Konishiroku Photo Ind Co Ltd | ハロゲン化銀写真感光材料 |
JPS63250385A (ja) | 1987-04-04 | 1988-10-18 | Tokuyama Soda Co Ltd | ハロゲン化複素環式化合物の製造方法 |
US5106862A (en) * | 1986-10-27 | 1992-04-21 | Aktiebolaget Hassle | Derivatives of benzimidazoles active as anti-ulcer agents |
WO2000042022A1 (fr) | 1999-01-13 | 2000-07-20 | Warner-Lambert Company | Les benzoheterocycles et leur utilisation comme inhibiteurs de mek |
WO2001005770A1 (fr) | 1999-07-21 | 2001-01-25 | Fujisawa Pharmaceutical Co., Ltd. | Derives de benzimidazolone et leur utilisation comme inhibiteurs de la phosphodiesterase |
WO2003077914A1 (fr) | 2002-03-13 | 2003-09-25 | Array Biopharma, Inc | Utilisation de derives de benzimidazole alkyles n3 en tant qu'inhibiteurs de mek |
WO2007002092A1 (fr) * | 2005-06-23 | 2007-01-04 | Array Biopharma Inc. | Procede snar de preparation de composes de benzimidazole |
WO2007053131A2 (fr) | 2004-06-04 | 2007-05-10 | Affinium Pharmaceuticals, Inc. | Agents thérapeutiques et méthodes pour les fabriquer et les utiliser |
WO2008055950A1 (fr) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | Nouveaux inhibiteurs de la glutaminyl-cyclase |
WO2008128985A1 (fr) | 2007-04-18 | 2008-10-30 | Probiodrug Ag | Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase |
Family Cites Families (548)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5736816A (ja) | 1980-08-14 | 1982-02-27 | Toshiba Corp | Chodendokoirunoseizohoho |
JPS57192573A (en) | 1981-05-25 | 1982-11-26 | Hochiki Co | Fire fighting agent |
JPS60165712A (ja) | 1984-02-08 | 1985-08-28 | パイオニア株式会社 | 可変調整部品の自動調整方法 |
JPS6126111A (ja) | 1984-07-16 | 1986-02-05 | Shin Meiwa Ind Co Ltd | 産業用ロボツト |
JPS6137764A (ja) | 1984-07-31 | 1986-02-22 | Suntory Ltd | 抗プロリルエンドペプチダ−ゼ活性を有する新規生理活性化合物 |
JPS6152021A (ja) | 1984-08-22 | 1986-03-14 | Fujitsu Ltd | スケルチ回路 |
JPS6172439A (ja) | 1984-09-18 | 1986-04-14 | Sanyo Electric Co Ltd | デ−タ転送方式 |
JPH0623190B2 (ja) | 1985-04-16 | 1994-03-30 | サントリー株式会社 | インヒビタ−活性を有するn−アシルピロリジン誘導体及びその製法並びに用途 |
EP0201743B1 (fr) | 1985-04-16 | 1992-04-01 | Suntory Limited | Dérivés dipeptidiques d'acides gras, procédé de préparation, composition pharmaceutique et utilisation |
DE3680578D1 (de) | 1985-04-16 | 1991-09-05 | Suntory Ltd | Dipeptid-derivate, verfahren zur herstellung, pharmazeutische zusammensetzungen und ihre anwendung. |
JPS62114957A (ja) | 1985-11-13 | 1987-05-26 | Suntory Ltd | プロリルエンドペプチダ−ゼ阻害作用を有する新規ピロリジン誘導体およびその製法並びに用途 |
JPH0714878B2 (ja) | 1985-11-14 | 1995-02-22 | サントリー株式会社 | ピロリジンアミドを有効成分とするプロリルエンドペプチダーゼ阻害剤 |
JPH0764834B2 (ja) | 1985-11-29 | 1995-07-12 | サントリー株式会社 | プロリルエンドペプチダーゼ阻害活性を有する新規ピロリジンアミド誘導体およびその製法並びに用途 |
CA1320734C (fr) | 1986-02-04 | 1993-07-27 | Suntory Limited | Derive pyrrolidineamide d'acide acylamine; composition pharmaceutique a base de ce derive |
US5198458A (en) | 1986-02-04 | 1993-03-30 | Suntory Limited | Pyrrolidineamide derivatives of acylamino acid and pharmaceutical composition containing the same |
CA1334092C (fr) | 1986-07-11 | 1995-01-24 | David John Carini | Imidazoles bloquant les recepteurs de l'angiotensine ii |
JPS6386485A (ja) | 1986-09-30 | 1988-04-16 | Agency Of Ind Science & Technol | トンネル型ジヨセフソン接合素子 |
US5223482A (en) | 1986-11-17 | 1993-06-29 | Scios Nova Inc. | Recombinant Alzheimer's protease inhibitory amyloid protein and method of use |
JPH08806B2 (ja) | 1986-11-18 | 1996-01-10 | サントリー株式会社 | プロリルエンドペプチダ−ゼ阻害作用を有する新規ピロリジンアミド誘導体 |
US5254550A (en) | 1986-11-20 | 1993-10-19 | Ono Pharmaceutical Co., Ltd. | Prolinal derivatives and pharmaceutical compositions thereof |
ES2058089T3 (es) | 1986-11-20 | 1994-11-01 | Ono Pharmaceutical Co | Un procedimiento para la preparacion de un nuevo derivado de prolinal. |
JPS63162672A (ja) | 1986-12-25 | 1988-07-06 | Ono Pharmaceut Co Ltd | 新規なプロリナ−ル誘導体、それらの製造方法およびそれらを含有する抗健忘症剤 |
ES2046195T3 (es) | 1986-12-29 | 1994-02-01 | Ono Pharmaceutical Co., Ltd. | Un procedimiento para la preparacion de los derivados de prolinal. |
US5262431A (en) | 1986-12-29 | 1993-11-16 | Ono Pharmaceutical Co., Ltd. | Prolinal derivatives and pharmaceutical compositions thereof |
JPH089591B2 (ja) | 1986-12-29 | 1996-01-31 | 小野薬品工業株式会社 | 新規なプロリナール誘導体 |
ATE87306T1 (de) | 1987-02-04 | 1993-04-15 | Ono Pharmaceutical Co | Prolinalderivate. |
DE3875361T2 (de) | 1987-02-23 | 1993-03-25 | Ono Pharmaceutical Co | Thiazolidin-derivate. |
JPS6442465A (en) | 1987-08-07 | 1989-02-14 | Wakunaga Pharma Co Ltd | N-acylprolylpyrrolidine derivative, production and use thereof |
US4857524A (en) | 1987-08-08 | 1989-08-15 | Kissei Pharmaceutical Co., Ltd. | Thiazolidine compounds and therapeutic method |
JP2649237B2 (ja) | 1988-03-07 | 1997-09-03 | キッセイ薬品工業 株式会社 | チアゾリジン誘導体 |
JP2515558B2 (ja) | 1987-09-10 | 1996-07-10 | 株式会社ヤクルト本社 | 新規なペプチドおよびそれを有効成分とする抗健忘症剤 |
CA1339014C (fr) | 1987-10-08 | 1997-03-25 | Ronald E. Majocha | Anticorps pour peptide a4-amyloide |
JPH0742309B2 (ja) | 1987-11-30 | 1995-05-10 | キッセイ薬品工業株式会社 | チアゾリジン誘導体 |
JPH01250370A (ja) | 1987-12-23 | 1989-10-05 | Zeria Pharmaceut Co Ltd | 新規アミノ酸イミド誘導体、製法ならびに用途 |
US5053414A (en) | 1988-04-08 | 1991-10-01 | Ono Pharmaceutical Co., Ltd. | Heterocyclic compounds |
US5328899A (en) | 1988-07-15 | 1994-07-12 | The Salk Institute For Biological Studies | NPY peptide analogs |
ZA896376B (en) | 1988-08-26 | 1990-05-30 | Merrell Dow Pharma | Neuropeptide y agonists |
ZA896374B (en) | 1988-08-26 | 1990-05-30 | Merrell Dow Pharma | Neuropeptide y antagonists |
JP2531989B2 (ja) | 1988-09-14 | 1996-09-04 | 吉富製薬株式会社 | ピリジン化合物 |
CA2004028C (fr) | 1988-12-08 | 1998-09-22 | Motoki Torizuka | Derives condenses de benzene |
JPH02207070A (ja) | 1989-02-07 | 1990-08-16 | Zeria Pharmaceut Co Ltd | アミノ酸イミド誘導体、それを含有する医薬及び該化合物の製造中間体 |
EP0419683A4 (en) | 1989-04-13 | 1992-03-11 | Japan Tobacco Inc. | New amino acid derivatives having prolylendopeptidase inhibitor activity |
WO1990012871A1 (fr) | 1989-04-14 | 1990-11-01 | Research Foundation For Mental Hygiene, Inc. | Anticorps monoclonal sv17-6e10 specifique de la proteine amyloide cerebrovasculaire |
WO1990012870A1 (fr) | 1989-04-14 | 1990-11-01 | Research Foundation For Mental Hygiene, Inc. | Anticorps monoclonal du peptide amyloide |
DE69034103T2 (de) | 1989-06-14 | 2004-07-15 | Smithkline Beecham Corp. | Imidazoalkensäure |
DE3939797A1 (de) | 1989-12-01 | 1991-06-06 | Basf Ag | Neue vom neuropeptid y abgeleitete peptide |
US4985560A (en) | 1990-01-12 | 1991-01-15 | American Home Products Corporation | Pyridazino(4,5-b)indolizines |
DE122010000024I1 (de) | 1990-02-19 | 2010-07-08 | Novartis Ag | Acylverbindungen |
JPH04211648A (ja) | 1990-07-27 | 1992-08-03 | Nippon Kayaku Co Ltd | ケト酸アミド誘導体 |
JPH03255080A (ja) | 1990-03-05 | 1991-11-13 | Yoshitomi Pharmaceut Ind Ltd | ベンゼン化合物 |
NZ237476A (en) | 1990-03-20 | 1994-01-26 | Sanofi Sa | N-substituted heterocyclic compounds and pharmaceutical compositions. |
US5073549A (en) | 1990-03-22 | 1991-12-17 | Bristol-Myers Squibb Company | BU-4164E - A and B, prolyl endopeptidase inhibitors and their methods of use |
US4999349A (en) | 1990-03-22 | 1991-03-12 | Bristol-Myers Squibb Co. | BU-4164E - A and B, prolyl endopeptidase inhibitors |
US5196444A (en) | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
WO1991018891A1 (fr) | 1990-06-04 | 1991-12-12 | Pfizer Inc. | Amides de pyrrolidine et de thiazolidine aromatiques |
AU643300B2 (en) | 1990-06-07 | 1993-11-11 | Zeria Pharmaceutical Co., Ltd. | Novel arylalkanoylamine derivative and drug containing the same |
JPH05186498A (ja) | 1991-12-27 | 1993-07-27 | Japan Tobacco Inc | プロリン誘導体 |
US5506256A (en) | 1990-07-27 | 1996-04-09 | Yoshitomi Pharmaceutical Industries, Ltd. | Proline derivatives possessing prolyl endopeptidase-inhibitory activity |
EP0468469A2 (fr) | 1990-07-27 | 1992-01-29 | Japan Tobacco Inc. | Dérivés de proline |
JPH04235162A (ja) | 1990-08-09 | 1992-08-24 | Zeria Pharmaceut Co Ltd | 新規コハク酸アミド誘導体およびそれを含有する医薬 |
JPH04208299A (ja) | 1990-11-30 | 1992-07-29 | Ajinomoto Co Inc | プロリルエンドペプチターゼ阻害ペプチド |
IE920540A1 (en) | 1991-02-21 | 1992-08-26 | Sankyo Co | 1-biphenylmethylimidazole derivatives, their preparation and¹their therapetuic use |
US5104880A (en) | 1991-05-01 | 1992-04-14 | Mayo Foundation For Medical Education And Research | Huperzine a analogs as acetylcholinesterase inhibitors |
WO1992021333A2 (fr) | 1991-05-24 | 1992-12-10 | Pharmavene, Inc. | Traitement des symptomes de sevrage et de manque dus a des drogues au moyen d'inhibiteurs d'oxydase de monoamine de type b |
ATE157988T1 (de) | 1991-06-20 | 1997-09-15 | Snow Brand Milk Products Co Ltd | Neuartige prolyl-endopeptidase-inhibitoren sna- 115 und sna-115t, ihre herstellung, und hierbei verwendete stämme |
DE4121975A1 (de) | 1991-07-03 | 1993-01-07 | Basf Ag | Thermoplastische formmassen auf der basis von polycarbonaten, styrol/acrylnitril-polymerisaten und polyolefinen |
HUT66324A (en) | 1991-07-29 | 1994-11-28 | Warner Lambert Co | Quinazoline derivatives as acetylcholinesterase inhibitors and pharmaceutical compositions containing them |
TW226375B (fr) | 1991-10-24 | 1994-07-11 | American Home Prod | |
EP0672054A4 (fr) | 1991-12-19 | 1996-02-07 | Garvan Inst Med Res | Nouvelle molecule inhibant la fonction biologique du neuropeptide tyrosine. |
JPH05301826A (ja) | 1991-12-24 | 1993-11-16 | Snow Brand Milk Prod Co Ltd | プロリルエンドペプチダーゼ阻害剤 |
JPH05201970A (ja) | 1992-01-24 | 1993-08-10 | Japan Tobacco Inc | 新規プロリン誘導体 |
JP3318622B2 (ja) | 1992-05-27 | 2002-08-26 | 独立行政法人産業技術総合研究所 | プロリルエンドペプチダーゼ阻害剤 |
GB9212308D0 (en) | 1992-06-10 | 1992-07-22 | Ici Plc | Therapeutic compositions |
GB9213215D0 (en) | 1992-06-20 | 1992-08-05 | Wellcome Found | Peptides |
JPH06116284A (ja) | 1992-10-02 | 1994-04-26 | Yamanouchi Pharmaceut Co Ltd | 新規ペプチド |
CA2146333A1 (fr) | 1992-10-05 | 1994-04-14 | Tomio Kimura | Derive de la pyrimidine |
US5260286A (en) | 1992-10-16 | 1993-11-09 | Japan Tobacco, Inc. | 2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists |
EP0670309A1 (fr) | 1992-11-20 | 1995-09-06 | Japan Tobacco Inc. | Compose inhibant la prolyle endopeptidase et utilisation pharmaceutique de ce dernier |
US5354758A (en) | 1992-12-16 | 1994-10-11 | Japan Tobacco Inc. | Benzomorphans useful as NMDA receptor antagonists |
JPH06192298A (ja) | 1992-12-24 | 1994-07-12 | Mitsui Toatsu Chem Inc | 新規機能性ペプチド |
DE4326465A1 (de) | 1993-01-20 | 1995-02-09 | Thomae Gmbh Dr K | Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
EP1308461A3 (fr) | 1993-01-25 | 2004-02-11 | Takeda Chemical Industries, Ltd. | Anticorps contre des bèta-amyloides ou leurs dérivés, et leurs utilisations |
JPH06234693A (ja) | 1993-02-09 | 1994-08-23 | Snow Brand Milk Prod Co Ltd | 新規イソテトラセノン系物質及びその製造法 |
FR2701480B1 (fr) | 1993-02-15 | 1995-05-24 | Sanofi Elf | Composés à groupe sulfamoyle et amidino, leur procédé de préparation et les compositions pharmaceutiques les contenant. |
EP0611769A1 (fr) | 1993-02-16 | 1994-08-24 | Merrell Dow Pharmaceuticals Inc. | Inhibiteurs d'acétylcholinerase silylés |
WO1994020476A1 (fr) | 1993-03-02 | 1994-09-15 | Fujisawa Pharmaceutical Co., Ltd. | Nouveau compose heterocyclique |
FR2702150B1 (fr) | 1993-03-03 | 1995-04-07 | Rhone Poulenc Rorer Sa | Application de dérivés de 2H-1,2-4-benzothiadiazine-3(4H)-one-1,1-dioxyde comme antagonistes non compétitifs du récepteur NMDA. |
FR2703050B1 (fr) | 1993-03-24 | 1995-04-28 | Adir | Nouveaux dérivés bicycliques azotés, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
EP0627400A1 (fr) | 1993-06-04 | 1994-12-07 | Merrell Dow Pharmaceuticals Inc. | Inhibiteurs aromatiques d'acétylcholinesterase |
JPH11501281A (ja) | 1993-06-18 | 1999-02-02 | ユニバーシティ オブ シンシナティ | 神経ペプチドyアンタゴニスト及びアゴニスト |
AU6983894A (en) | 1993-06-30 | 1995-01-24 | Zeria Pharmaceutical Co., Ltd. | Thiazolidine derivative and medicine containing the same |
FR2707643B1 (fr) | 1993-07-16 | 1995-08-11 | Rhone Poulenc Rorer Sa | Dérivés d'imidazo[1,2-a]pyrazine-4-one, leur préparation et les médicaments les contenant. |
FR2707645B1 (fr) | 1993-07-16 | 1995-08-11 | Rhone Poulenc Rorer Sa | Dérivés d'imidazo[1,2-a]pirazine-4-one, leur préparation et les médicaments les contenant. |
DE69428703T2 (de) | 1993-07-23 | 2002-05-29 | Zaidan Hojin Biseibutsu | Pyrrolidin derivate |
WO1995004723A1 (fr) * | 1993-08-04 | 1995-02-16 | Yamanouchi Pharmaceutical Co., Ltd. | Derive d'imidazolylalkylamine et composition pharmaceutique contenant ledit derive |
FR2711993B1 (fr) | 1993-11-05 | 1995-12-01 | Rhone Poulenc Rorer Sa | Médicaments contenant des dérivés de 7H-imidazol[1,2-a]pyrazine-8-one, les nouveaux composés et leur préparation. |
ES2179093T3 (es) | 1993-12-02 | 2003-01-16 | Merrell Pharma Inc | Inhibidores de la prolilendopeptidasa. |
IL111785A0 (en) | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
FR2717811B1 (fr) | 1994-03-28 | 1996-04-26 | Rhone Poulenc Rorer Sa | Dérivés d'imidazo[1,2-a]pyrazine-4-one, leur préparation et les médicaments les contenant. |
FR2717805B1 (fr) | 1994-03-28 | 1996-05-10 | Rhone Poulenc Rorer Sa | Dérivés de 5H-indeno[1,2-b]pyrazine-2,3-dione, leur préparation et les médicaments les contenant . |
FR2717813B1 (fr) | 1994-03-28 | 1996-05-10 | Rhone Poulenc Rorer Sa | Dérivés d'imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one, leur préparation et les médicaments les contenant . |
FR2717812B1 (fr) | 1994-03-28 | 1996-05-10 | Rhone Poulenc Rorer Sa | Indeno[1,2-e]pyrazine-4-ones, leur préparation et les médicaments les contenant. |
JPH07267988A (ja) | 1994-03-31 | 1995-10-17 | Yamanouchi Pharmaceut Co Ltd | 新規ペプチド |
GB9410320D0 (en) | 1994-05-24 | 1994-07-13 | Fisons Corp | Novel therapeutic method |
GB9418443D0 (en) | 1994-09-13 | 1994-11-02 | Pfizer Ltd | Therapeutic agents |
US5663192A (en) | 1994-10-20 | 1997-09-02 | Eli Lilly And Company | Heterocyclic neuropeptide Y receptor antagonists |
WO1996012489A1 (fr) | 1994-10-20 | 1996-05-02 | Eli Lilly And Company | Antagonistes du recepteur du neuropeptide y bicyclique |
US6562862B1 (en) | 1994-10-20 | 2003-05-13 | Eli Lilly And Company | Methods of inhibiting physiological conditions associated with an excess of neuropeptide Y |
FR2726275B1 (fr) | 1994-11-02 | 1996-12-06 | Rhone Poulenc Rorer Sa | Spiro heterocycle-imidazo(1,2-a)indeno(1,2-e)pyrazine)-4'- ones, leur preparation et les medicaments les contenants |
IL116584A0 (en) | 1994-12-29 | 1996-03-31 | Res Dev Foundation | Novel flavin adenine dinucleotide analogue inhibitors of monoamine oxidase |
US5691368A (en) | 1995-01-11 | 1997-11-25 | Hoechst Marion Roussel, Inc. | Substituted oxazolidine calpain and/or cathepsin B inhibitors |
GB9500601D0 (en) | 1995-01-12 | 1995-03-01 | Wellcome Found | Modified peptides |
US5786180A (en) | 1995-02-14 | 1998-07-28 | Bayer Corporation | Monoclonal antibody 369.2B specific for β A4 peptide |
US5552411A (en) | 1995-05-26 | 1996-09-03 | Warner-Lambert Company | Sulfonylquinolines as central nervous system and cardiovascular agents |
IL117997A0 (en) | 1995-06-07 | 1996-10-31 | Pfizer | Neuropeptide Y1 specific ligands |
US5554621A (en) | 1995-06-07 | 1996-09-10 | Bristol-Myers Squibb Company | Dihydropyridine NPY antagonists: nitrogen heterocyclic derivatives |
US5635503A (en) | 1995-06-07 | 1997-06-03 | Bristol-Myers Squibb Company | Dihydropyridine npy antagonists: piperazine derivatives |
US5668151A (en) | 1995-06-07 | 1997-09-16 | Bristol-Myers Squibb Company | Dihydropyridine NPY antagonists: piperidine derivatives |
JP3727383B2 (ja) | 1995-07-31 | 2005-12-14 | 月桂冠株式会社 | プロリルエンドペプチダーゼ阻害剤 |
TR199700334T1 (tr) | 1995-09-01 | 1997-08-21 | Lilly Co Eli | Indolil nöropeptid y reseptör antagonistleri. |
AU6966696A (en) | 1995-10-05 | 1997-04-28 | Warner-Lambert Company | Method for treating and preventing inflammation and atherosclerosis |
ES2100129B1 (es) | 1995-10-11 | 1998-02-16 | Medichem Sa | Nuevos compuestos aminopiridinicos policiclicos inhibidores de acetilcolinesterasa, procedimiento para su preparacion y su utilizacion. |
DE19544685A1 (de) | 1995-11-30 | 1997-06-05 | Thomae Gmbh Dr K | Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
DE19544687A1 (de) | 1995-11-30 | 1997-06-05 | Thomae Gmbh Dr K | Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
DE19544686A1 (de) | 1995-11-30 | 1997-06-05 | Thomae Gmbh Dr K | Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
AU7692696A (en) | 1995-12-01 | 1997-06-27 | Novartis Ag | Heteroaryl derivatives |
AU7692996A (en) | 1995-12-01 | 1997-06-27 | Ciba-Geigy Ag | Receptor antagonists |
WO1997020820A1 (fr) | 1995-12-01 | 1997-06-12 | Novartis Ag | Composes heteroaryles |
AU1328197A (en) | 1995-12-01 | 1997-06-19 | Synaptic Pharmaceutical Corporation | Aryl sulfonamide and sulfamide derivatives and uses thereof |
AU7692896A (en) | 1995-12-01 | 1997-06-27 | Novartis Ag | Quinazolin-2,4-diazirines as NPY receptor antagonist |
JPH09157253A (ja) | 1995-12-12 | 1997-06-17 | Yamanouchi Pharmaceut Co Ltd | 新規アミノ酸誘導体 |
ZA9610741B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
ZA9610745B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
ZA9610736B (en) | 1995-12-22 | 1997-06-27 | Warner Lambert Co | 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists |
JP2000501107A (ja) | 1996-01-09 | 2000-02-02 | イーライ・リリー・アンド・カンパニー | ベンズイミダゾリル神経ペプチドy受容体アンタゴニスト |
GB9605027D0 (en) | 1996-03-09 | 1996-05-08 | Pfizer Ltd | Quinoxalinediones |
US5662723A (en) | 1996-03-22 | 1997-09-02 | Libbey Glass Inc. | Apparatus and method for forming a decorative pattern on glassware having an edge |
JP4109718B2 (ja) | 1996-04-12 | 2008-07-02 | アベンティス・ファーマスーティカルズ・インコーポレイテッド | アセチルコリンエステラーゼ阻害剤および鎮痛剤としてのイサチン誘導体 |
DE19616486C5 (de) | 1996-04-25 | 2016-06-30 | Royalty Pharma Collection Trust | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
WO1997046250A1 (fr) | 1996-06-04 | 1997-12-11 | Synaptic Pharmaceutical Corporation | Procedes de modification du comportement alimentaire, composes utiles dans lesdits procedes, et adn codant un recepteur y5 atypique hypothalamique de neuropeptide y/peptide yy |
US6335323B2 (en) | 1996-07-05 | 2002-01-01 | The Wwk Trust | Compositions for the treatment of peripheral neuropathies containing antidepressants and/or monoamine oxidase inhibitors and/or vitamin B12 and/or precursors or inducers of a neurotransmitter |
CA2260982A1 (fr) | 1996-07-23 | 1998-01-29 | Neurogen Corporation | Derives benzylamine substitues et nouvelle classe de ligands specifiques des neuropeptides y1 |
EP0915859B1 (fr) | 1996-07-23 | 2003-01-02 | Neurogen Corporation | Derives benzylamine substitues et nouvelle classe de ligands specifiques des neuropeptides y1 |
WO1998003494A1 (fr) | 1996-07-23 | 1998-01-29 | Neurogen Corporation | Derives benzylamine a substitution amido et amino, et classe de ligands specifiques du neuropeptide y1 |
WO1998005337A1 (fr) | 1996-08-01 | 1998-02-12 | Cocensys, Inc. | Utilisation de ligands de recepteurs gaba et nmda pour le traitement des cephalees de la migraine |
AU4054197A (en) | 1996-08-14 | 1998-03-06 | Warner-Lambert Company | 2-phenyl benzimidazole derivatives as mcp-1 antagonists |
JP2001502296A (ja) | 1996-08-23 | 2001-02-20 | アラネックス コーポレーション | ニューロペプチド―yリガンド |
JP3880664B2 (ja) | 1996-09-04 | 2007-02-14 | 月桂冠株式会社 | プロリルエンドペプチダーゼ阻害ペプチド |
AU4424697A (en) | 1996-09-11 | 1998-04-02 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | The use of functional n-methyl-d-aspartate antagonists to ameliorate or prevent aminoglycoside-induced ototoxicity |
AU4944297A (en) | 1996-10-08 | 1998-05-05 | Novartis Ag | Modulation of apoptosis |
FR2754709B1 (fr) | 1996-10-23 | 1999-03-05 | Sanofi Sa | Composition cosmetique contenant un antagoniste des recepteurs du neuropeptide gamma et alpha 2 antagonistes susceptibles d'etre incorpores dans une telle composition |
US6011155A (en) | 1996-11-07 | 2000-01-04 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
TW492957B (en) | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
AU5716898A (en) | 1997-01-08 | 1998-08-03 | Warner-Lambert Company | Acetylcholinesterase inhibitors in combination with muscarinic agonists for the treatment of alzheimer's disease |
US20030068316A1 (en) | 1997-02-05 | 2003-04-10 | Klein William L. | Anti-ADDL antibodies and uses thereof |
JP2894445B2 (ja) | 1997-02-12 | 1999-05-24 | 日本たばこ産業株式会社 | Cetp活性阻害剤として有効な化合物 |
AU6417198A (en) | 1997-03-13 | 1998-09-29 | Bioresearch Ireland a division of Eolas - The Irish Science and Technology Agency | Cytoprotective agents comprising monoamine oxidase inhibitors |
SI0994728T1 (sl) | 1997-04-09 | 2009-02-28 | Intellect Neurosciences Inc | Rekombinantna protitelesa, specifična za beta-amiloidne konce, kodirana z DNA ter postopki za njihovo uporabo |
US8173127B2 (en) | 1997-04-09 | 2012-05-08 | Intellect Neurosciences, Inc. | Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof |
EP0975584B1 (fr) | 1997-04-16 | 2002-09-25 | Arqule, Inc. | Synthese et utilisation de derives et ensembles de alpha-cetoamide |
CA2289190A1 (fr) | 1997-05-07 | 1998-11-12 | Algos Pharmaceutical Corporation | Composition et methode associant un antidepresseur et un antagoniste de recepteur nmda pour traiter la douleur neuropathique |
AU7472798A (en) | 1997-05-07 | 1998-11-27 | Algos Pharmaceutical Corporation | Cox-2 inhibitors in combination with nmda-blockers for treating pain |
CN1136187C (zh) | 1997-06-30 | 2004-01-28 | 莫茨股份公司 | 1-氨基烷基环己烷nmda受体拮抗剂 |
GB9716657D0 (en) | 1997-08-07 | 1997-10-15 | Zeneca Ltd | Chemical compounds |
GB9716879D0 (en) | 1997-08-08 | 1997-10-15 | Shire Int Licensing Bv | Treatment of attention deficit disorders |
AU7696098A (en) | 1997-08-11 | 1999-03-01 | Algos Pharmaceutical Corporation | Substance p inhibitors in combination with nmda-blockers for treating pain |
SE9703376D0 (sv) | 1997-09-18 | 1997-09-18 | Astra Ab | A new combination |
SE9703414D0 (sv) | 1997-09-23 | 1997-09-23 | Astra Ab | New compounds |
TWI239847B (en) | 1997-12-02 | 2005-09-21 | Elan Pharm Inc | N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease |
US7179892B2 (en) | 2000-12-06 | 2007-02-20 | Neuralab Limited | Humanized antibodies that recognize beta amyloid peptide |
US7964192B1 (en) | 1997-12-02 | 2011-06-21 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidgenic disease |
EP2823812A1 (fr) | 1998-02-02 | 2015-01-14 | Trustees Of Tufts College | Inhibiteurs de dipeptidylpeptidase-IV pour leur utilisation dans le traitement du diabète de type II |
EP1062222A1 (fr) | 1998-03-09 | 2000-12-27 | Fondatech Benelux N.V. | Modulateurs de la serine peptidase |
US6007841A (en) | 1998-03-13 | 1999-12-28 | Algos Pharmaceutical Corporation | Analgesic composition and method for treating pain |
GB9805561D0 (en) | 1998-03-16 | 1998-05-13 | Merck Sharp & Dohme | A combination of therapeutic agents |
US6541208B1 (en) | 1998-03-17 | 2003-04-01 | University Of Maryland Biotechnology Institute | Diagnostic method for distinguishing HIV-associated dementia from other forms of dementia |
DE19812331A1 (de) | 1998-03-20 | 1999-09-23 | Merck Patent Gmbh | Piperidinderivate |
US6054451A (en) | 1998-04-21 | 2000-04-25 | Algos Pharmaceutical Corporation | Analgesic composition and method for alleviating pain |
WO1999057120A1 (fr) | 1998-05-04 | 1999-11-11 | Neotherapeutics, Inc. | Nouvelle hypoxanthine 9-substituee apparentee a la serotonine |
AU3879899A (en) | 1998-05-04 | 1999-11-23 | Neotherapeutics, Inc. | Novel dopamine-like 9-substituted hypoxanthine and methods of use |
NZ507727A (en) | 1998-05-21 | 2003-11-28 | Univ Tennessee Res Foundation | Methods for amyloid removal using anti-amloid antibodies |
DE19823831A1 (de) | 1998-05-28 | 1999-12-02 | Probiodrug Ges Fuer Arzneim | Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen |
DE19828114A1 (de) | 1998-06-24 | 2000-01-27 | Probiodrug Ges Fuer Arzneim | Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV |
DE19828113A1 (de) | 1998-06-24 | 2000-01-05 | Probiodrug Ges Fuer Arzneim | Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV |
PE20000728A1 (es) | 1998-06-26 | 2000-08-21 | Cocensys Inc | Heterociclos 4-bencil piperidina alquilsulfoxido y su uso como antagonistas receptores subtipo-selectivo nmda |
US6262081B1 (en) | 1998-07-10 | 2001-07-17 | Dupont Pharmaceuticals Company | Composition for and method of treating neurological disorders |
DE19834591A1 (de) | 1998-07-31 | 2000-02-03 | Probiodrug Ges Fuer Arzneim | Verfahren zur Steigerung des Blutglukosespiegels in Säugern |
US6218383B1 (en) | 1998-08-07 | 2001-04-17 | Targacept, Inc. | Pharmaceutical compositions for the prevention and treatment of central nervous system disorders |
IL125809A (en) | 1998-08-17 | 2005-08-31 | Finetech Lab Ltd | Process and intermediates for production of donepezil and related compounds |
IT1304904B1 (it) | 1998-09-11 | 2001-04-05 | Eisai Co Ltd | Derivati anticolinesterasici per il trattamento delle sindromidolorose funzionali e/o organiche |
PL348107A1 (en) | 1998-10-16 | 2002-05-06 | Janssen Pharmaceutica Nv | Therapy for improving cognition |
CA2351224A1 (fr) | 1998-11-12 | 2000-05-25 | Algos Pharmaceutical Corporation | Utilisation d'une combinaison d'inhibiteurs de cox-2 et de substances bloquant les recepteurs de nmda pour le traitement de la douleur |
WO2000030446A1 (fr) | 1998-11-23 | 2000-06-02 | Bonnie Davis | Formulations de dosage d'inhibiteurs de l'acetylcholinesterase |
WO2000030674A1 (fr) | 1998-11-26 | 2000-06-02 | Ferring Bv | Agents neuropeptide y-y4 utilises dans le traitement des troubles de la reproduction |
JP2002531502A (ja) | 1998-12-11 | 2002-09-24 | デイビス、ボニー | 視床下部−下垂体−生殖腺軸変調に於けるアセチルコリンエステラーゼ阻害剤の使用 |
GB9902452D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
GB9902453D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
GB9902461D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
GB9902455D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
GB9902459D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
WO2000056711A1 (fr) | 1999-03-23 | 2000-09-28 | Sumitomo Pharmaceuticals Co., Ltd. | Compose d'acide indole-2-carboxylique tricyclique utilise comme antagoniste du recepteur nmda |
EP1173486A1 (fr) | 1999-04-15 | 2002-01-23 | Merck Frosst Canada & Co. | Anticorps reconnaissant l'app clivee par les caspases et leurs procedes d'utilisation |
US6121311A (en) | 1999-04-28 | 2000-09-19 | Japan Tobacco Inc. | Method for treating cocainism |
CA2373035A1 (fr) | 1999-05-05 | 2000-11-16 | Scott Dax | Ligands de recepteurs du neuropeptide y derives de 3a,4,5,9b-tetrahydro-1h-benz[e]indol-2-yl amine, utilises pour le traitement de l'obesite et d'autres etats pathologiques |
JP3148739B2 (ja) | 1999-05-19 | 2001-03-26 | ドーマー株式会社 | プロリルエンドペプチダーゼ阻害剤 |
DE60040024D1 (de) | 1999-06-16 | 2008-10-02 | Boston Biomedical Res Inst | Immunologische kontrolle des beta-amyloid gehaltes in vivo |
US6110949A (en) | 1999-06-24 | 2000-08-29 | Novartis Ag | N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
US6172081B1 (en) | 1999-06-24 | 2001-01-09 | Novartis Ag | Tetrahydroisoquinoline 3-carboxamide derivatives |
US6107317A (en) | 1999-06-24 | 2000-08-22 | Novartis Ag | N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
US6524616B1 (en) | 1999-06-25 | 2003-02-25 | Wake Forest University Health Services | Compositions and methods for treating or preventing neurodegeneration and cognitive decline and dysfunction associated with alzheimer's disease, aging, other dementia related disorders and estrogen deficiency related conditions |
US6316449B1 (en) | 1999-07-08 | 2001-11-13 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists |
DE19936719A1 (de) | 1999-08-06 | 2001-02-15 | Gruenenthal Gmbh | Substituierte 1,5-Dihydropyrrol-2-on-Derivate |
DE19936521A1 (de) | 1999-08-06 | 2001-02-15 | Gruenenthal Gmbh | Substituierte Pyrrolidin-2,3,4-trion-3-oxim-Derivate |
EP1307219A4 (fr) | 1999-08-13 | 2005-04-06 | Univ Columbia | Procedes d'inhibition de la liaison de la fibrille a feuillets beta au recepteur rage, et leurs consequences |
EP1078632A1 (fr) | 1999-08-16 | 2001-02-28 | Sanofi-Synthelabo | Utilisation des inhibiteurs de monoamine oxydases dans la fabrication d'un médicament contre l'obésité |
DE19940130A1 (de) | 1999-08-24 | 2001-03-01 | Probiodrug Ges Fuer Arzneim | Neue Effektoren der Dipeptidyl Peptidase IV zur topischen Anwendung |
TWI292316B (en) | 1999-10-11 | 2008-01-11 | Sod Conseils Rech Applic | Pharmaceutical composition of thiazole derivatives intended to inhibit mao and/or lipidic peroxidation and/or to act as modulators of sodium channels and the use thereof |
UA72558C2 (uk) | 1999-11-01 | 2005-03-15 | Мерц Фарма Гмбх Унд Ко. Кгаа | 1-аміноалкілциклогексанові антагоністи рецептора nmda |
CA2390231A1 (fr) | 1999-11-12 | 2001-05-17 | Paul Jackson | Inhibiteurs de la dipeptidyl peptidase iv; methodes de fabrication et d'utilisation desdits inhibiteurs |
GB9928330D0 (en) | 1999-11-30 | 2000-01-26 | Ferring Bv | Novel antidiabetic agents |
JP2003520266A (ja) | 2000-01-24 | 2003-07-02 | メルク シャープ エンド ドーム リミテッド | γ−セクレターゼ阻害薬 |
EP1254113A1 (fr) | 2000-01-24 | 2002-11-06 | Novo Nordisk A/S | 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv |
CA2399080C (fr) | 2000-02-03 | 2013-05-21 | Millennium Pharmaceuticals, Inc. | Anticorps humanises anti-ccr2 et procedes d'utilisation de ces anticorps |
KR100767146B1 (ko) | 2000-02-24 | 2007-10-15 | 워싱톤 유니버시티 | Aβ 펩티드를 격리시키는 인간화 항체 |
GB0005251D0 (en) | 2000-03-03 | 2000-04-26 | Merck Sharp & Dohme | Therapeutic compounds |
US20030144255A1 (en) | 2000-03-06 | 2003-07-31 | Bain Allen I | Compositions for prevention and treatment of dementia |
US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
US6992081B2 (en) | 2000-03-23 | 2006-01-31 | Elan Pharmaceuticals, Inc. | Compounds to treat Alzheimer's disease |
US7119085B2 (en) | 2000-03-23 | 2006-10-10 | Elan Pharmaceuticals, Inc. | Methods to treat alzheimer's disease |
GB0008710D0 (en) | 2000-04-07 | 2000-05-31 | Merck Sharp & Dohme | Therapeutic compounds |
EP1285656A4 (fr) | 2000-04-13 | 2006-07-12 | Eisai Co Ltd | Inhibiteurs d'acetylcholinesterases contenant des sels de 1-benzyl-pyridinium |
GB0010188D0 (en) | 2000-04-26 | 2000-06-14 | Ferring Bv | Inhibitors of dipeptidyl peptidase IV |
GB0010183D0 (en) | 2000-04-26 | 2000-06-14 | Ferring Bv | Inhibitors of dipeptidyl peptidase IV |
EE200200612A (et) | 2000-04-26 | 2004-06-15 | Warner-Lambert Company | Tsükloheksüülamiini derivaadid kui alatüübi selektiivsed NMDA-retseptori antagonistid |
US20010036949A1 (en) | 2000-05-09 | 2001-11-01 | Coe Jotham Wadsworth | Pharmaceutical composition and method of treatment of diseases of cognitive dysfunction in a mammal |
JP2003535073A (ja) | 2000-06-01 | 2003-11-25 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | サブタイプ選択性nmdaレセプター拮抗物質としてのシクロヘキシルアミン誘導体 |
ES2243500T3 (es) | 2000-06-06 | 2005-12-01 | Warner-Lambert Company Llc | Ciclohexilaminas biciclicas y uso como antegonistas del receptor nmda. |
AU783522B2 (en) | 2000-06-22 | 2005-11-03 | Pharmos Corporation | Novel non-psychotropic cannabinoids |
GB0015488D0 (en) | 2000-06-23 | 2000-08-16 | Merck Sharp & Dohme | Therapeutic agents |
US6713276B2 (en) | 2000-06-28 | 2004-03-30 | Scios, Inc. | Modulation of Aβ levels by β-secretase BACE2 |
US6686449B2 (en) | 2000-06-30 | 2004-02-03 | Pharmacia & Upjohn Company | Mutant presenilin 1 polypeptides |
NZ523005A (en) | 2000-06-30 | 2004-11-26 | Elan Pharm Inc | Compounds to treat alzheimer's disease |
AU6895801A (en) | 2000-07-04 | 2002-01-14 | Novo Nordisk As | Heterocyclic compounds, which are inhibitors of the enzyme dpp-iv |
GB0016681D0 (en) | 2000-07-06 | 2000-08-23 | Merck Sharp & Dohme | Therapeutic compounds |
US6556971B1 (en) | 2000-09-01 | 2003-04-29 | Snap-On Technologies, Inc. | Computer-implemented speech recognition system training |
AU2001293056A1 (en) | 2000-09-25 | 2002-04-08 | Motorwiz, Inc. | Model-based machine diagnostics and prognostics using theory of noise and communications |
US20020151591A1 (en) | 2000-10-17 | 2002-10-17 | Anabella Villalobos | Combination use of acetylcholinesterase inhibitors and GABAa inverse agonists for the treatment of cognitive disorders |
HU227197B1 (en) | 2000-10-24 | 2010-10-28 | Richter Gedeon Nyrt | Nmda receptor antagonist carboxylic acid amide derivatives and pharmaceutical compositions containing them |
DE60112957T2 (de) | 2000-11-02 | 2006-05-18 | Merck Sharp & Dohme Ltd., Hoddesdon | Sulfamide als gamma-secretase-inhibitoren |
US20020150948A1 (en) | 2000-11-03 | 2002-10-17 | Gerardo Castillo | Antibody PTI-HS7 for treatment of alzheimer's disease and other amyloidoses and parkinson's disease |
TWI243162B (en) | 2000-11-10 | 2005-11-11 | Taisho Pharmaceutical Co Ltd | Cyanopyrrolidine derivatives |
TWI255272B (en) | 2000-12-06 | 2006-05-21 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
US6495335B2 (en) | 2000-12-07 | 2002-12-17 | Mario Chojkier | Compositions and methods for diagnosing alzheimer's disease |
US6670364B2 (en) | 2001-01-31 | 2003-12-30 | Telik, Inc. | Antagonists of MCP-1 function and methods of use thereof |
TWI245761B (en) | 2001-03-01 | 2005-12-21 | Telik Inc | Antagonists of MCP-1 function and methods of use thereof |
AU2002250256B2 (en) | 2001-03-08 | 2008-04-03 | Emory University | pH-dependent NMDA receptor antagonists |
US6649196B2 (en) | 2001-03-12 | 2003-11-18 | Mayo Foundation For Medical Education And Research | Methods of reducing β-amyloid polypeptides |
US6815175B2 (en) | 2001-03-16 | 2004-11-09 | Cornell Research Foundation, Inc. | Anti-amyloid peptide antibody based diagnosis and treatment of a neurological disease or disorder |
US6677365B2 (en) | 2001-04-03 | 2004-01-13 | Telik, Inc. | Antagonists of MCP-1 function and methods of use thereof |
US6573287B2 (en) | 2001-04-12 | 2003-06-03 | Bristo-Myers Squibb Company | 2,1-oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method |
EP2165714B1 (fr) | 2001-04-30 | 2013-10-23 | Eli Lilly And Company | Anticorps humanisés reconnaissant le peptide amyloide béta |
ATE409047T1 (de) | 2001-04-30 | 2008-10-15 | Lilly Co Eli | Humanisierte antikörper |
FR2824825B1 (fr) | 2001-05-15 | 2005-05-06 | Servier Lab | Nouveaux derives d'alpha-amino-acides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
SI20922A (sl) | 2001-05-18 | 2002-12-31 | Krka Tovarna Zdravil, D.D., Novo Mesto | Monoklonsko protitelo, ki nevtralizira aktivnost katepsina B, in njegove uporabe |
US6562783B2 (en) | 2001-05-30 | 2003-05-13 | Neurologic, Inc. | Phosphinylmethyl and phosphorylmethyl succinic and glutauric acid analogs as β-secretase inhibitors |
AU2002314914A1 (en) | 2001-06-01 | 2002-12-16 | Elan Pharmaceuticals, Inc. | Hydroxy alkyl amine derivatives as beta-secretase inhibitors and their use for the treatment of alzheimer's disease and similar diseases |
ES2257555T3 (es) | 2001-06-20 | 2006-08-01 | MERCK & CO., INC. | Inhibidores de dipeptidilpeptidasa para el tratamiento de la diabetes. |
CA2450579A1 (fr) | 2001-06-20 | 2003-01-03 | Merck & Co., Inc. | Inhibiteurs de dipeptidyle peptidase pour le traitement du diabete |
GB0115517D0 (en) | 2001-06-25 | 2001-08-15 | Ferring Bv | Novel antidiabetic agents |
ATE370943T1 (de) | 2001-06-27 | 2007-09-15 | Smithkline Beecham Corp | Fluoropyrrolidine als dipeptidyl-peptidase inhibitoren |
DE10150203A1 (de) | 2001-10-12 | 2003-04-17 | Probiodrug Ag | Peptidylketone als Inhibitoren der DPIV |
WO2003002595A2 (fr) | 2001-06-27 | 2003-01-09 | Probiodrug Ag | Nouveaux inhibiteurs de dipeptidylpeptidase iv et leurs utilisations en tant qu'agents anti-cancereux |
WO2003002530A2 (fr) | 2001-06-27 | 2003-01-09 | Smithkline Beecham Corporation | Pyrrolidines servant d'inhibiteurs de dipeptidyl peptidase |
EP1862457B1 (fr) | 2001-06-27 | 2010-01-20 | SmithKline Beecham Corporation | Fluoropyrrolidines en tant qu'inhibiteurs de la peptidase dipeptidyle |
CN1688599A (zh) | 2001-06-27 | 2005-10-26 | 前体生物药物股份有限公司 | 二肽基肽酶iv抑制剂的新用途 |
DE10154689A1 (de) | 2001-11-09 | 2003-05-22 | Probiodrug Ag | Substituierte Aminoketonverbindungen |
WO2003002122A1 (fr) | 2001-06-27 | 2003-01-09 | Elan Pharmaceuticals, Inc. | Derives de beta-hydroxyamine utiles dans le traitement de la maladie d'alzheimer |
JP2005502624A (ja) | 2001-07-03 | 2005-01-27 | ノボ ノルディスク アクティーゼルスカブ | 糖尿病を治療するための、dpp−ivを阻害するプリン誘導体 |
UA74912C2 (en) | 2001-07-06 | 2006-02-15 | Merck & Co Inc | Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes |
CZ2004233A3 (cs) | 2001-07-24 | 2004-12-15 | Richter Gedeon Vegyészeti Gyár Rt. | Nové amidové sloučeniny karboxylové kyseliny |
US20040234990A1 (en) | 2001-07-31 | 2004-11-25 | Hiroto Komano | Method of screening alzheimer's disease-associated gene |
US7122675B2 (en) | 2001-08-03 | 2006-10-17 | Schering Corporation | Gamma secretase inhibitors |
JP4729717B2 (ja) | 2001-08-03 | 2011-07-20 | 株式会社医学生物学研究所 | GM1ガングリオシド結合型アミロイドβタンパク質を認識する抗体、及び該抗体をコードするDNA |
HUP0600673A3 (en) | 2001-08-03 | 2011-08-29 | Schering Corp | Tetrahydroquinolin derivatives as gamma secretase inhibitors nad pharmaceutical compositions containing them |
CA2451998A1 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Anticorps anti-$g(a)$g(b) |
US20060073149A1 (en) | 2001-08-17 | 2006-04-06 | Bales Kelly R | Rapid improvement of cognition in condition related to abeta |
MXPA04001959A (es) | 2001-08-30 | 2005-02-17 | Johnson & Johnson | Tratamiento de la demencia y trastornos de la memoria con anticonvulsivantes e. inhibidores de acetilcolinesterasa. |
WO2003024942A1 (fr) | 2001-09-14 | 2003-03-27 | Mitsubishi Pharma Corporation | Derive thiazolidine et son utilisation medicamenteuse |
EP1463727A2 (fr) | 2001-09-19 | 2004-10-06 | Novo Nordisk A/S | Composes heterocycliques constituant des inhibiteurs de l'enzyme dpp-iv |
GB0125445D0 (en) | 2001-10-23 | 2001-12-12 | Ferring Bv | Protease Inhibitors |
JP4547152B2 (ja) | 2001-10-23 | 2010-09-22 | オクラホマ メディカル リサーチ ファウンデーション | β−セクレターゼ阻害剤および使用方法 |
GB0125446D0 (en) | 2001-10-23 | 2001-12-12 | Ferring Bv | Novel anti-diabetic agents |
US6861440B2 (en) | 2001-10-26 | 2005-03-01 | Hoffmann-La Roche Inc. | DPP IV inhibitors |
CN100488982C (zh) | 2001-11-02 | 2009-05-20 | 迪尔基因国际有限公司 | 与β-淀粉样蛋白结合并引起蛋白质构象转变的单克隆抗体的制备方法 |
EP1447095B1 (fr) | 2001-11-02 | 2012-06-13 | Kensuke Egashira | Prophylactiques et/ou remedes pour le traitement de l'arteriosclerose apres transplantation dans le cas de rejet de greffe |
US20050208050A1 (en) | 2001-11-09 | 2005-09-22 | Gerd Multhaup | Compounds for the diagnosis/prevention/treatment of alzheimer's disease |
BR0214295A (pt) | 2001-11-19 | 2004-11-09 | Elan Pharm Inc | Composto, método para tratar um paciente que tem ou prevenir um paciente de adquirir uma doença ou condição, e, método para produzir um composto |
CA2466841A1 (fr) | 2001-11-21 | 2003-06-05 | New York University | Polypeptides immunogenes synthetiques ne formant pas de depots et peptides homologues destines a des repetitions amyloide $g(b), proteine prion, amyline, $g(a)-synucleine, ou polyglutamine pour induction d'une reponse immunitaire a ceux-ci |
US7727964B2 (en) | 2001-11-26 | 2010-06-01 | Trustees Of Tufts College | Peptidomimetic inhibitors of post-proline cleaving enzymes |
WO2003048204A1 (fr) | 2001-12-06 | 2003-06-12 | Takeda Chemical Industries, Ltd. | Gene associe a la maladie d'alzheimer, sa proteine et son utilisation |
WO2003051374A2 (fr) | 2001-12-17 | 2003-06-26 | New York State Office Of Mental Health | SEQUESTRATION DE Aβ DANS LA REGION PERIPHERIQUE EN L'ABSENCE D'AGENTS IMMUNOMODULATEURS COMME APPROCHE THERAPEUTIQUE POUR LE TRAITEMENT OU LA PREVENTION DES MALADIES LIEES A LA BETA-AMYLOIDE |
EP1465854A4 (fr) | 2001-12-19 | 2005-06-08 | Atherogenics Inc | Derives de chalcone et leur utilisation dans le traitement de maladies |
WO2003055514A1 (fr) | 2001-12-21 | 2003-07-10 | Antigenics Inc. | Compositions comprenant des reactifs immunoreactifs et des saponosides et techniques d'utilisation de ces compositions |
AU2002360732A1 (en) | 2001-12-26 | 2003-07-24 | Guilford Pharmaceuticals | Change inhibitors of dipeptidyl peptidase iv |
US6727261B2 (en) | 2001-12-27 | 2004-04-27 | Hoffman-La Roche Inc. | Pyrido[2,1-A]Isoquinoline derivatives |
WO2003057204A2 (fr) | 2002-01-08 | 2003-07-17 | Nordic Bioscience A/S | Prevention ou attenuation de l'auto-immunite |
EP1467729A1 (fr) | 2002-01-18 | 2004-10-20 | The Genetics Company Inc. | Inhibiteurs de beta-secretase |
EP1534310A4 (fr) | 2002-01-31 | 2006-05-31 | Univ Tel Aviv Future Tech Dev | Peptides, anticorps diriges contre les maladies associees a l'amyloide et procedes utilisant ces peptides et ces anticorps en vue de diagnostiquer et de traiter ces maladies |
US20040171614A1 (en) | 2002-02-06 | 2004-09-02 | Schering-Plough Corporation | Novel gamma secretase inhibitors |
TW200302717A (en) | 2002-02-06 | 2003-08-16 | Schering Corp | Novel gamma secretase inhibitors |
WO2003068748A1 (fr) | 2002-02-13 | 2003-08-21 | F. Hoffmann-La Roche Ag | Nouveaux derives de pyridine et de quinoline |
BR0307665A (pt) | 2002-02-13 | 2005-01-04 | Hoffmann La Roche | Compostos, processo para a sua manufatura, composições farmacêuticas que compreendem os mesmos, método para o tratamento e/ou profilaxia de enfermidades associadas com dpp iv e utilização dos compostos |
AR038568A1 (es) | 2002-02-20 | 2005-01-19 | Hoffmann La Roche | Anticuerpos anti-a beta y su uso |
HUP0200849A2 (hu) | 2002-03-06 | 2004-08-30 | Sanofi-Synthelabo | N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra |
MY139983A (en) | 2002-03-12 | 2009-11-30 | Janssen Alzheimer Immunotherap | Humanized antibodies that recognize beta amyloid peptide |
ATE373660T1 (de) | 2002-03-25 | 2007-10-15 | Merck & Co Inc | Heterocyclische beta-aminoverbindungen als inhibitoren der dipeptidylpeptidase zur behandlung bzw. prävention von diabetes |
ES2297141T3 (es) | 2002-03-29 | 2008-05-01 | EISAI R&D MANAGEMENT CO., LTD. | Derivados de (1-indanona)-(1,2,3,6-tetrahidropiridina). |
US20070134247A9 (en) | 2002-04-12 | 2007-06-14 | Ramot At Tel Aviv University Ltd. | Prevention of brain inflammation as a result of induced autoimmune response |
ATE514707T1 (de) | 2002-04-19 | 2011-07-15 | Univ Toronto | Immunologisches verfahren und zusammensetzungen für die behandlung der krankheit von alzheimer |
CN1319987C (zh) | 2002-04-24 | 2007-06-06 | 森启 | γ-分泌酶抑制剂 |
ES2315494T3 (es) | 2002-04-26 | 2009-04-01 | Schering Corporation | Antagonistas muscarinicos. |
AU2003230392A1 (en) | 2002-05-17 | 2003-12-12 | Merck And Co., Inc. | Beta-secretase inhibitors |
MXPA04011762A (es) | 2002-05-31 | 2005-03-31 | Lundbeck & Co As H | Una combinacion de antagonista de nmda e inhibidores de acetilcolinesterasa para el tratamiento de la enfermedad de alzheimer. |
AU2003233010A1 (en) | 2002-06-04 | 2003-12-19 | Pfizer Products Inc. | Process for the preparation of 3,3,4,4-tetrafluoropyrrolidine and derivatives thereof |
AU2003232405A1 (en) | 2002-06-04 | 2003-12-19 | Pfizer Products Inc. | Flourinated cyclic amides as dipeptidyl peptidase iv inhibitors |
KR100985160B1 (ko) | 2002-06-06 | 2010-10-05 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 신규한 축합된 이미다졸 유도체 |
CA2491520A1 (fr) | 2002-06-19 | 2003-12-31 | Surface Specialties, S.A. | Compositions pulverulentes pour revetements semi-lustres |
AU2003248259A1 (en) | 2002-07-10 | 2004-02-02 | Yamanouchi Pharmaceutical Co., Ltd. | Novel azetidine derivative or salt thereof |
CA2490818A1 (fr) | 2002-07-15 | 2004-01-22 | Merck & Co., Inc. | Inhibiteurs de piperidino pyrimidine dipeptidyl peptidase utilises dans le traitement du diabete |
US20040019118A1 (en) | 2002-07-19 | 2004-01-29 | Khalid Iqbal | NMDA receptor antagonists and their use in inhibiting abnormal hyperphosphorylation of microtubule associated protein tau |
US7557137B2 (en) | 2002-08-05 | 2009-07-07 | Bristol-Myers Squibb Company | Gamma-lactams as beta-secretase inhibitors |
BRPI0313648B8 (pt) | 2002-08-21 | 2021-05-25 | Boehringer Ingelheim Pharma | 8-[3-amino-piperidin-1-il]-xantinas, seus sais fisiologicamente compatíveis, seus usos e seus processos de preparação, bem como medicamentos que as contêm e seus processos de preparação |
DE10238477A1 (de) | 2002-08-22 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Purinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
DE10238470A1 (de) | 2002-08-22 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
ES2201929B1 (es) | 2002-09-12 | 2005-05-16 | Araclon Biotech, S.L. | Anticuerpos policlonales, metodo de preparacion y uso de los mismos. |
AU2003270643A1 (en) | 2002-09-12 | 2004-04-30 | The Regents Of The University Of California | Immunogens and corresponding antibodies specific for high molecular weight aggregation intermediates common to amyloids formed from proteins of differing sequence |
CN1681926A (zh) | 2002-09-12 | 2005-10-12 | 财团法人化学及血清疗法研究所 | 人的抗人mcp-1抗体和该抗体的片段 |
CA2768674A1 (fr) | 2002-09-19 | 2004-04-01 | Abbott Laboratories | Compositions pharmaceutiques utiles comme inhibiteurs de la peptidase-iv dipeptidyl (dpp-iv) |
US20050282871A1 (en) | 2002-09-20 | 2005-12-22 | Burrill Ii Leland C | 3-(3,5-Disubstituted-4-hydroxyphenyl)propionamide derivatives as cathepsin b inhibitors |
US7273889B2 (en) | 2002-09-25 | 2007-09-25 | Innovative Drug Delivery Systems, Inc. | NMDA receptor antagonist formulation with reduced neurotoxicity |
WO2004029629A1 (fr) | 2002-09-27 | 2004-04-08 | Janssen Pharmaceutica N.V. | Anticorps monoclonaux beta-amyloide n-11 tronques, compositions, methodes et utilisations |
AU2003279728B2 (en) | 2002-10-01 | 2007-09-27 | Northwestern University | Amyloid beta-derived diffusible ligands (addls), addl-surrogates, addl-binding molecules, and uses thereof |
GB0223039D0 (en) | 2002-10-04 | 2002-11-13 | Merck Sharp & Dohme | Therapeutic compounds |
GB0223038D0 (en) | 2002-10-04 | 2002-11-13 | Merck Sharp & Dohme | Therapeutic compounds |
JP4491346B2 (ja) | 2002-10-07 | 2010-06-30 | メルク・シャープ・エンド・ドーム・コーポレイション | 抗糖尿病ベータアミノ複素環ジペプチジルペプチダーゼ阻害剤 |
AU2003269850A1 (en) | 2002-10-08 | 2004-05-04 | Novo Nordisk A/S | Hemisuccinate salts of heterocyclic dpp-iv inhibitors |
GB0223494D0 (en) | 2002-10-09 | 2002-11-13 | Neuropharma Sa | Dual binding site acetylcholinesterase inhibitors for the treatment of alzheimer's disease |
JP2006519762A (ja) | 2002-10-09 | 2006-08-31 | ライナット ニューロサイエンス コーポレイション | アミロイドβペプチド及びその組成物に対する抗体を使用して、アルツハイマー病を治療する方法 |
EP1556362B1 (fr) | 2002-10-18 | 2008-03-26 | Merck & Co., Inc. | Inhibiteurs de dipeptidylpeptidase heterocyclique beta-amino destines au traitement ou a la prevention de diabetes |
KR100777904B1 (ko) | 2002-10-24 | 2007-11-28 | 메르츠 파마 게엠베하 운트 코. 카가아 | 1-아미노시클로헥산 유도체 및 아세틸콜린에스테라제 저해제를 포함하는 약학적 제품 및 이를 이용한 복합 치료 |
US20040082543A1 (en) | 2002-10-29 | 2004-04-29 | Pharmacia Corporation | Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain |
AU2003285296A1 (en) | 2002-10-30 | 2004-05-25 | Nordic Bioscience A/S | Coumpounds modulating the activity of gapdh and/or iamt |
WO2004041795A1 (fr) | 2002-10-30 | 2004-05-21 | Guilford Pharmaceuticals Inc. | Nouveaux inhibiteurs de dipeptidyl peptidase iv |
GB0225474D0 (en) | 2002-11-01 | 2002-12-11 | Merck Sharp & Dohme | Therapeutic agents |
FR2846667B1 (fr) | 2002-11-06 | 2004-12-31 | Pasteur Institut | Fragments variables d'anticorps de camelides a chaine unique diriges contre le peptide beta-amyloide 1-42 et leurs applications pour le diagnostic et le traitement des maladies neuroagregatives |
AU2003290577B2 (en) | 2002-11-07 | 2008-12-11 | Merck Sharp & Dohme Corp. | Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
CA2505098A1 (fr) | 2002-11-12 | 2004-05-27 | Merck & Co., Inc. | Inhibiteurs de beta-secretase phenylcarboxamide utilises dans le traitement de la maladie d'alzheimer |
AU2002952946A0 (en) | 2002-11-27 | 2002-12-12 | Fujisawa Pharmaceutical Co., Ltd. | Dpp-iv inhibitor |
JP2006510630A (ja) | 2002-12-04 | 2006-03-30 | メルク エンド カムパニー インコーポレーテッド | 糖尿病を治療又は予防するためのジペプチジルペプチダーゼ阻害剤としてのフェニルアラニン誘導体 |
US7420079B2 (en) | 2002-12-09 | 2008-09-02 | Bristol-Myers Squibb Company | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
AU2003303239A1 (en) | 2002-12-19 | 2004-07-14 | Atherogenics, Inc. | Process of making chalcone derivatives |
US20060052382A1 (en) | 2002-12-20 | 2006-03-09 | Duffy Joseph L | 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
EP1583750B1 (fr) | 2003-01-07 | 2013-02-27 | Merck Sharp & Dohme Corp. | Inhibiteurs de bêta-sécrétase macrocyclique pour traiter la maladie d'Alzheimer |
WO2004064778A2 (fr) | 2003-01-17 | 2004-08-05 | Merck & Co. Inc. | Derives d'acide 3-amino-4-phenylbutanoique utilises comme inhibiteurs de la dipeptidyl peptidase pour le traitement ou la prevention du diabete |
AU2004210149A1 (en) | 2003-01-31 | 2004-08-19 | Merck & Co., Inc. | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
DE10303974A1 (de) | 2003-01-31 | 2004-08-05 | Abbott Gmbh & Co. Kg | Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung |
NZ567324A (en) | 2003-02-01 | 2009-08-28 | Wyeth Corp | Active immunization to generate antibodies to soluble A-beta |
MXPA05008172A (es) | 2003-02-04 | 2005-10-05 | Hoffmann La Roche | Derivados de malonamida como inhibidores gamma-secretasa. |
ES2344645T3 (es) | 2003-02-10 | 2010-09-02 | Applied Molecular Evolution, Inc. | Moleculas de union al abeta. |
WO2004071454A2 (fr) | 2003-02-13 | 2004-08-26 | Guilford Pharmaceuticals Inc. | Composes d'azetidine substitues servant d'inhibiteurs de dipeptidyl peptidase iv |
BRPI0407597A (pt) | 2003-02-18 | 2006-02-21 | Roskamp Res Llc | propriedades anti-angiogênicas e anti-tumorais de inibidores de beta e gama secretase |
US8663650B2 (en) | 2003-02-21 | 2014-03-04 | Ac Immune Sa | Methods and compositions comprising supramolecular constructs |
AU2003207881A1 (en) | 2003-02-28 | 2004-09-17 | Aic | Dipeptidyl peptidase inhibitors |
WO2004076434A1 (fr) | 2003-02-28 | 2004-09-10 | Aic | Inhibiteurs de dipeptidyl peptidases |
EP1454627A1 (fr) | 2003-03-06 | 2004-09-08 | MyoContract Ltd. | Dérivés alpha-cétocarbonyliques comme inhibiteurs de la calpaine |
WO2004084830A2 (fr) | 2003-03-21 | 2004-10-07 | Buck Institute | Méthode de traitement de la maladie d'alzheimer |
US20040191334A1 (en) | 2003-03-24 | 2004-09-30 | Pang-Chui Shaw | Use of transhinone derivates as cholinesterase inhibitors in treating related diseases |
US7687625B2 (en) | 2003-03-25 | 2010-03-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
MXPA05010171A (es) | 2003-03-28 | 2005-12-12 | Acadia Pharm Inc | Agonistas de receptor muscarinico m1 para manejo del dolor. |
US20050129695A1 (en) | 2003-03-28 | 2005-06-16 | Marc Mercken | Anti-amyloid antibodies, compositions, methods and uses |
AU2004230895B2 (en) | 2003-04-09 | 2010-09-09 | Wyeth | Derivatives of 2-(8,9-dioxo-2,6-diazabicyclo(5.2.0)non-1(7)-en-2-yl)alkyl phosphonic acid and their use as N-methyl-D-aspartate (NMDA) receptor antagonists |
GB0308318D0 (en) | 2003-04-10 | 2003-05-14 | Merck Sharp & Dohme | Therapeutic agents |
GB0308382D0 (en) | 2003-04-10 | 2003-05-21 | Univ Cambridge Tech | Therapeutic methods and means |
WO2004089362A1 (fr) | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | 2-cyanopyrroles et leurs analogues en tant qu'inhibiteurs de dipeptidylpeptidase-iv (dp-iv) |
ZA200508439B (en) | 2003-05-05 | 2007-03-28 | Probiodrug Ag | Medical use of inhibitors of glutaminyl and glutamate cyclases |
WO2004098625A2 (fr) | 2003-05-05 | 2004-11-18 | Probiodrug Ag | Utilisation d'effecteurs de glutaminyl- et de glutamate-cyclases |
WO2004099134A2 (fr) | 2003-05-05 | 2004-11-18 | Prosidion Ltd. | Inhibiteurs de la dp iv a base de glutaminyle |
ES2246105B1 (es) | 2003-05-08 | 2007-03-01 | Araclon Biotech, S.L. | Uso de anticuerpos para el tratamiento de enfermedades amiloideas. |
AU2003902260A0 (en) | 2003-05-09 | 2003-05-29 | Fujisawa Pharmaceutical Co., Ltd. | Dpp-iv inhibitor |
MXPA05012268A (es) | 2003-05-13 | 2006-02-10 | Schering Corp | N-arilsulfonilpiperidinas enlazadas como inhibidores de la gamma-secretasa. |
WO2004103993A1 (fr) | 2003-05-14 | 2004-12-02 | Syrrx, Inc. | Inhibiteurs de dipeptidyl peptidase |
JP2006528693A (ja) | 2003-05-14 | 2006-12-21 | メルク エンド カムパニー インコーポレーテッド | 糖尿病を治療又は予防するためのジペプチジルペプチダーゼ阻害剤としての3−アミノ−4−フェニルブタン酸誘導体 |
KR20060013404A (ko) | 2003-05-16 | 2006-02-09 | 머크 샤프 앤드 돔 리미티드 | γ-세크레타제 억제용 사이클릭 설폰아미드 |
EP2260844A1 (fr) | 2003-05-27 | 2010-12-15 | Merz Pharma GmbH & Co. KGaA | Combinaison d'un antagoniste de récepteur NMDA et d'un inhibiteur de la recapture sélective de la sérotonine pour le traitement de la dépression et d'autres troubles de l'humeur |
PE20050627A1 (es) | 2003-05-30 | 2005-08-10 | Wyeth Corp | Anticuerpos humanizados que reconocen el peptido beta amiloideo |
AU2003902828A0 (en) | 2003-06-05 | 2003-06-26 | Fujisawa Pharmaceutical Co., Ltd. | Dpp-iv inhibitor |
CN1798556A (zh) | 2003-06-06 | 2006-07-05 | 麦克公司 | 作为治疗或者预防糖尿病的二肽基肽酶抑制剂的稠合吲哚 |
AU2003902946A0 (en) | 2003-06-12 | 2003-06-26 | Fujisawa Pharmaceutical Co., Ltd. | Dpp-iv inhibitor |
WO2004112701A2 (fr) | 2003-06-17 | 2004-12-29 | Merck & Co., Inc. | Derives de cyclohexylglycine servant d'inhibiteurs de la dipeptidyl peptidase pour le traitement ou la prevention du diabete |
WO2005000848A1 (fr) | 2003-06-20 | 2005-01-06 | F. Hoffmann-La Roche Ag | Derives de pyrido[2,1-a]isoquinoline utilises comme inhibiteurs de dpp-iv |
CN101090901B (zh) | 2003-06-20 | 2010-12-15 | 霍夫曼-拉罗奇有限公司 | 作为dpp-iv抑制剂的六氢吡啶并异喹啉类 |
CA2530927A1 (fr) | 2003-06-30 | 2005-01-06 | Tel Aviv University Future Technology Development L.P. | Peptides, anticorps diriges contre les maladies associees a l'amyloide et procedes d'utilisation pour le diagnostic et le traitement de ces maladies |
WO2005004802A2 (fr) | 2003-06-30 | 2005-01-20 | Merck & Co., Inc. | Inhibiteurs de la beta-secretase a base de n-alkyle phenylcarboxamide pour le traitement de la maladie d'alzheimer |
AU2004255191A1 (en) | 2003-07-01 | 2005-01-20 | Merck & Co., Inc. | Phenylcarboxylate beta-secretase inhibitors for the treatment of Alzheimer's disease |
WO2005007614A1 (fr) | 2003-07-03 | 2005-01-27 | The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services 6011 | Inhibiteurs d'oxydase de monoamine |
CN1852741A (zh) | 2003-07-16 | 2006-10-25 | Rvx治疗公司 | 下调TGF-β效应的化合物和方法 |
EP1671129A1 (fr) | 2003-07-21 | 2006-06-21 | Angiogenetics Sweden AB | Composes et methodes pour favoriser l'angiogenese, au moyen d'un inhibiteur de la gamma secretase et en inhibant la voie de la gamma secretase |
WO2005009421A2 (fr) | 2003-07-28 | 2005-02-03 | Merz Pharma Gmbh & Co. Kgaa | Utilisation de composes d'1-amino-alkylcyclohexane dans le traitement de l'hypersensibilite a la douleur |
EP1651623B1 (fr) | 2003-07-31 | 2008-12-17 | Merck & Co., Inc. | Hexahydrodiazepinones utilises en tant qu'inhibiteurs de la dipeptidyl peptidase iv pour le traitement ou la prevention du diabete |
US20050124016A1 (en) | 2003-08-01 | 2005-06-09 | Enh Research Institute | Antibodies specific for toxic amyloid beta protein oligomers |
GB0318447D0 (en) | 2003-08-05 | 2003-09-10 | Merck Sharp & Dohme | Therapeutic agents |
CN1867560A (zh) | 2003-08-13 | 2006-11-22 | 武田药品工株式会社 | 4-嘧啶酮衍生物及其作为肽基肽酶抑制剂的用途 |
JP2007502278A (ja) | 2003-08-14 | 2007-02-08 | メルク エンド カムパニー インコーポレーテッド | アルツハイマー病の治療のための大員環β−セクレターゼ阻害剤 |
WO2005018424A2 (fr) | 2003-08-18 | 2005-03-03 | Research Foundation For Mental Hygiene, Inc. | Anticorps specifiques de la proteine amyloide fibrillaire et procedure permettant de detecter des depots de proteines amyloides fibrillaires |
WO2005023762A1 (fr) | 2003-09-04 | 2005-03-17 | Abbott Laboratories | Derives de pyrrolidine-2-carbonitrile et leur utilisation comme inhibiteurs de la dipeptidyle peptidase-iv (dpp-iv) |
WO2005023858A1 (fr) | 2003-09-05 | 2005-03-17 | Cellzome Ag | Complexes proteiniques associes au traitement de la proteine precurseur amyloide |
EP1697342A2 (fr) | 2003-09-08 | 2006-09-06 | Takeda Pharmaceutical Company Limited | Inhibiteurs de dipeptidyle peptidase |
EP1699777B1 (fr) | 2003-09-08 | 2012-12-12 | Takeda Pharmaceutical Company Limited | Inhibiteurs de la dipeptidylpeptidase |
EP1666061A1 (fr) | 2003-09-09 | 2006-06-07 | Takeda Pharmaceutical Company Limited | Utilisation d'un anticorps |
TW200530157A (en) | 2003-09-09 | 2005-09-16 | Japan Tobacco Inc | Dipeptidyl peptidase iv inhibitor |
JP2007527865A (ja) | 2003-09-12 | 2007-10-04 | ザ・レジェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア | 種々の配列を有するタンパク質から形成されたアミロイドに共通の高分子量凝集中間体に特異的なモノクローナル抗体 |
GB0322140D0 (en) | 2003-09-22 | 2003-10-22 | Pfizer Ltd | Combinations |
ATE509917T1 (de) | 2003-09-24 | 2011-06-15 | Merck Sharp & Dohme | Gamma-secretase-inhibitoren |
US7829597B2 (en) | 2003-10-03 | 2010-11-09 | Merck, Sharp & Dohme, Inc. | Benzylether and benzylamino beta-secretase inhibitors for the treatment of alzheimer's disease |
DK1673347T3 (en) | 2003-10-06 | 2015-10-12 | Hoffmann La Roche | SUBSTITUTED DIBENZO-AZEPINE AND BENZO-DIAZEPINE DERIVATIVES USED AS GAMMA SECRETASE INHIBITORS |
BR0318533A (pt) | 2003-10-06 | 2006-09-12 | Torrent Pharmaceuticals Ltd | azolidinacarbonitrilas e seu uso como inibidores de dpp-iv |
US20070021414A1 (en) | 2003-10-08 | 2007-01-25 | Pfizer, Inc. | 1-'2-(4-Hydroxyphenyl)-2-hydroxyethyl!-piperidin-4-ol compounds as nmda receptor antagonists |
KR20120007079A (ko) | 2003-10-15 | 2012-01-19 | 프로비오드룩 아게 | 글루타미닐 및 글루타메이트 사이클라제 이펙터의 용도 |
EP2269608A3 (fr) | 2003-10-16 | 2011-02-16 | NeuroSearch AS | Compositions pharmaceutiques comprenants des inhibiteurs de récaptage de neurotransmitteurs monoamine et des inhibiteurs de l'acétylcholinestérase |
GB0324236D0 (en) | 2003-10-16 | 2003-11-19 | Astrazeneca Ab | Chemical compounds |
TW200519105A (en) | 2003-10-20 | 2005-06-16 | Lg Life Science Ltd | Novel inhibitors of DPP-IV, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent |
TW200526194A (en) | 2003-10-22 | 2005-08-16 | Merz Pharma Gmbh & Co Kgaa | The use of 1-aminocyclohexane derivatives to modify deposition of fibrillogenic Aβ peptides in amyloidopathies |
WO2006058720A2 (fr) | 2003-11-03 | 2006-06-08 | Probiodrug Ag | Nouveaux composes pour le traitement de troubles neurologiques |
JP2007510651A (ja) | 2003-11-04 | 2007-04-26 | メルク エンド カムパニー インコーポレーテッド | 糖尿病の治療又は予防のためのジペプチジルペプチダーゼ−iv阻害剤としての縮合フェニルアラニン誘導体 |
CN100497355C (zh) | 2003-11-11 | 2009-06-10 | 弗·哈夫曼-拉罗切有限公司 | 作为β-分泌酶抑制剂用于治疗阿尔茨海默氏病的次磷酸衍生物 |
PL1689757T3 (pl) | 2003-11-12 | 2015-05-29 | Sino Med Int Alliance Inc | Heterocykliczne związki kwasu boronowego |
CA2546142A1 (fr) | 2003-11-24 | 2005-06-09 | Merck & Co., Inc. | Inhibiteurs de benzylether et benzylamino de beta-secretase pour traiter la maladie d'alzheimer |
DE10355304A1 (de) | 2003-11-27 | 2005-06-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 8-(Piperazin-1-yl)-und 8-([1,4]Diazepan-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
UY28650A1 (es) | 2003-12-05 | 2005-02-28 | Forest Laboratories | Memantina para la prevencion o disminucion de la conducta suicida y para el tratamiento de la depresion mayor asociada con esta conducta |
EP1541148A1 (fr) | 2003-12-09 | 2005-06-15 | Graffinity Pharmaceuticals Aktiengesellschaft | Inhibiteurs de dpp-iv |
EP1541143A1 (fr) | 2003-12-09 | 2005-06-15 | Graffinity Pharmaceuticals Aktiengesellschaft | Inhibiteurs de dpp-iv |
WO2005058849A1 (fr) | 2003-12-15 | 2005-06-30 | Glenmark Pharmaceuticals Ltd. | Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procede de preparation et compositions les contenant |
AU2004311749A1 (en) | 2003-12-19 | 2005-07-21 | Merck & Co., Inc. | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of Alzheimer's disease |
AU2005205882A1 (en) | 2004-01-22 | 2005-08-04 | Neurosearch A/S | Pharmaceutical composition comprising a monoamine neurotransmitter re-uptake inhibitor and an N-methyl-D-aspartate (NMDA) receptors antagonist |
WO2005072705A1 (fr) | 2004-01-29 | 2005-08-11 | Neuromolecular, Inc. | Combinaison d'antagoniste de recepteur nmda et d'inhibiteur mao ou gadpf pour le traitement d'affections liees au systeme nerveux central |
WO2005075426A1 (fr) | 2004-02-03 | 2005-08-18 | Glenmark Pharmaceuticals Ltd. | Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procedes de preparation et compositions en comportant |
CN1918131B (zh) | 2004-02-05 | 2011-05-04 | 前体生物药物股份公司 | 谷氨酰胺酰基环化酶抑制剂 |
AU2005215775B2 (en) | 2004-02-13 | 2011-02-03 | Neuromolecular, Inc. | Combination of a NMDA receptor antagonist and an anti-depressive drug MAO-inhibitor or a GADPH-inhibitor for the treatment of psychiatric conditions |
US20050182044A1 (en) | 2004-02-17 | 2005-08-18 | Bruinsma Gosse B. | Combinatorial therapy with an acetylcholinesterase inhibitor and (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3,-b]indol-5-yl phenylcarbamate |
AU2005219508B2 (en) | 2004-02-18 | 2012-02-16 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a DPP inhibitor |
US7807157B2 (en) | 2004-02-20 | 2010-10-05 | Intellect Neurosciences Inc. | Monoclonal antibodies and use thereof |
KR20130016435A (ko) | 2004-02-23 | 2013-02-14 | 트러스티즈 오브 터프츠 칼리지 | 디펩티딜펩티다아제 ⅳ의 억제제 |
EP1593671A1 (fr) | 2004-03-05 | 2005-11-09 | Graffinity Pharmaceuticals AG | Inhibiteurs de la DPP-IV |
KR100844593B1 (ko) | 2004-03-09 | 2008-07-07 | 내셔날 헬스 리서치 인스티튜트 | 피롤리딘 화합물 |
MXPA06010571A (es) | 2004-03-15 | 2007-02-16 | Takeda Pharmaceutical | Inhibidores de dipeptidil peptidasa. |
WO2005092009A2 (fr) | 2004-03-19 | 2005-10-06 | Axonyx, Inc. | Inhibiteurs d'acetylcholinesterase et antagonistes de n-methyle-d-aspartate utiles dans le traitement de troubles cognitifs |
WO2005095339A1 (fr) | 2004-03-31 | 2005-10-13 | Pfizer Products Inc. | Dicyanopyrrolidines inhibiteurs de la dipeptidyl peptidase iv |
WO2005097103A2 (fr) | 2004-04-01 | 2005-10-20 | Axys Pharmaceuticals, Inc. | Traitement du diabete et du syndrome metabolique au moyen d'inhibiteurs de la cathepsine b |
EP1740570A2 (fr) | 2004-04-05 | 2007-01-10 | Schering Corporation | Nouveaux inhibiteurs de gamma secretase |
EP1740559B1 (fr) | 2004-04-20 | 2014-10-15 | Merck Sharp & Dohme Corp. | Derives de phenyle 1,3,5-substitues utiles comme inhibiteurs de la beta-secretase pour le traitement de la maladie d'alzheimer |
WO2005103043A1 (fr) | 2004-04-20 | 2005-11-03 | Merck & Co., Inc. | Composes derives de pyridyle substitues aux positions 2, 4, 6 utiles comme inhibiteurs de la beta-secretase dans le traitement de la maladie d'alzheimer |
WO2005102390A2 (fr) | 2004-04-22 | 2005-11-03 | Pfizer Japan, Inc. | Combinaisons comprenant des ligands alpha-2-delta et des antagonistes des recepteurs de nmda |
WO2005105133A2 (fr) | 2004-04-23 | 2005-11-10 | Massachusetts Eye And Ear Infirmary | Methodes et compositions de conservation de la viabilite de cellules photoreceptrices |
JPWO2005105998A1 (ja) | 2004-04-27 | 2008-07-31 | 財団法人化学及血清療法研究所 | ヒト抗アミロイドβペプチド抗体およびその抗体フラグメント |
WO2005108382A1 (fr) | 2004-05-04 | 2005-11-17 | Merck & Co., Inc. | Derives de 1,2,4-oxadiazole en tant qu'inhibiteurs de la dipeptidylpeptidase-iv dans le traitement ou la prevention de diabetes |
ES2327857T3 (es) | 2004-05-12 | 2009-11-04 | Pfizer Products Inc. | Derivados de prolina y su uso como inhibidores de la dipeptidil peptidasa iv. |
CN1964940A (zh) | 2004-05-13 | 2007-05-16 | 默克公司 | 可用作β-分泌酶抑制剂用于治疗阿尔茨海默氏病的苯基羧酰胺化合物 |
US7671073B2 (en) | 2004-05-18 | 2010-03-02 | Merck Sharp & Dohme Corp. | Cyclohexylalanine derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
EP1598341A1 (fr) | 2004-05-21 | 2005-11-23 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | Inhibiteurs de DPP-IV |
WO2005118555A1 (fr) | 2004-06-04 | 2005-12-15 | Takeda Pharmaceutical Company Limited | Inhibiteurs de la dipeptidyl peptidase |
EP1766396B1 (fr) | 2004-06-07 | 2010-08-11 | Ramot at Tel-Aviv University Ltd. | Procede d'immunisation passive contre des maladies ou des troubles caracterise(e)s par agregation amyloide a risque diminue de neuroinflammation |
EP1604662A1 (fr) | 2004-06-08 | 2005-12-14 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | Derivés de la benzyl amine du acide carboxylique (2R) de la 1-[(3R)-Amino-4-(2-fluoro-phenyl)-butyl]-pyrrolidine et composés similaires pour l'utilisation comme inhibiteurs de la peptidase dipeptidyl IV (DPP-IV) pour le traitement de la diabetes mellitus de type 2 |
EP1604980A1 (fr) | 2004-06-08 | 2005-12-14 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | Inhibiteurs de DPP-IV |
EP1604989A1 (fr) | 2004-06-08 | 2005-12-14 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | Inhibiteurs de DPP-IV |
US7714021B2 (en) | 2004-06-15 | 2010-05-11 | Merck & Co., Inc. | Pyrrolidin-3-yl compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease |
GB0413389D0 (en) | 2004-06-16 | 2004-07-21 | Astrazeneca Ab | Chemical compounds |
SE0401601D0 (sv) | 2004-06-21 | 2004-06-21 | Bioarctic Neuroscience Ab | Protofibril specific antibodies and uses thereof |
AU2005265148B2 (en) | 2004-06-21 | 2011-01-20 | Merck Sharp & Dohme Corp. | Aminocyclohexanes as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
WO2006085961A2 (fr) | 2004-06-30 | 2006-08-17 | Centocor, Inc. | Anticorps anti-mcp-1, compositions, procedes et utilisations |
AR050994A1 (es) | 2004-06-30 | 2006-12-13 | Schering Corp | N-arilsulfonilaminas heterociclicas sustituidas como inhibidores de gamma-secretasas, y composicion farmaceutica en base al compuesto |
JP2008513732A (ja) | 2004-07-02 | 2008-05-01 | ノースウエスタン ユニバーシティ | アミロイドβ(Abeta)の病理学的なアセンブリを標的とするモノクローナル抗体 |
EP1778220A1 (fr) | 2004-07-12 | 2007-05-02 | Phenomix Corporation | Composes cyano contraints |
WO2006019965A2 (fr) | 2004-07-16 | 2006-02-23 | Takeda San Diego, Inc. | Inhibiteurs de la dipeptidyl peptidase |
WO2006014638A2 (fr) | 2004-07-19 | 2006-02-09 | The General Hospital Corporation | Anticorps anti-oligomeres reticules de la proteine $g(b)-amyloide |
WO2006008661A2 (fr) | 2004-07-19 | 2006-01-26 | Neurochem (International) Limited | Methodes diagnostiques d'amylose affectant de multiples organes |
JP2008507538A (ja) | 2004-07-22 | 2008-03-13 | シェーリング コーポレイション | 置換アミドβセクレターゼインヒビター |
CN101027297B (zh) | 2004-07-28 | 2010-09-08 | 先灵公司 | 大环β-分泌酶抑制剂 |
HUP0401523A3 (en) | 2004-07-29 | 2007-05-02 | Richter Gedeon Vegyeszet | Indole-2-carboxamide derivatives, pharmaceutical compositions containing them and process for producing them |
WO2006036291A2 (fr) | 2004-07-30 | 2006-04-06 | Rinat Neuroscience Corp. | Anticorps anti peptide amyloide beta, et leurs procedes d'utilisation |
EP1623983A1 (fr) | 2004-08-05 | 2006-02-08 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | Composés hétérocycliques utilisables comme inhibiteurs de DPP-IV |
KR20070073743A (ko) | 2004-08-11 | 2007-07-10 | 미쓰비시 가가꾸 가부시키가이샤 | 항체 및 그 이용 |
ATE473742T1 (de) | 2004-08-23 | 2010-07-15 | Merck Sharp & Dohme | Kondensierte triazolderivate als dipeptidylpeptidase-iv-hemmer zur behandlung bzw. prävention von diabetes |
AU2005276631A1 (en) | 2004-08-25 | 2006-03-02 | Santhera Pharmaceuticals (Schweiz) Ag | Alpha-keto carbonyl calpain inhibitors |
AU2005276635A1 (en) | 2004-08-25 | 2006-03-02 | Santhera Pharmaceuticals (Schweiz) Ag | Alpha-keto carbonyl calpain inhibitors |
US7388007B2 (en) | 2004-08-26 | 2008-06-17 | Bristol-Myers Squibb Company | Gamma-lactams as beta-secretase inhibitors |
US7335491B2 (en) | 2004-08-27 | 2008-02-26 | Wyeth Research Ireland Limited | Production of anti-abeta |
CA2579472A1 (fr) | 2004-09-14 | 2006-03-23 | The Genetics Company, Inc. | Derives d'hydrazone et leur utilisation comme inhibiteurs de la beta-secretase |
WO2006034277A1 (fr) | 2004-09-17 | 2006-03-30 | Comentis, Inc. | Composes bicycliques inhibant l'activite de la beta-secretase et procedes d'utilisation associes |
WO2006034296A2 (fr) | 2004-09-17 | 2006-03-30 | Comentis, Inc. | Composes amino inhibant l'activite de la beta-secretase et methodes d'utilisation |
US20060246075A1 (en) | 2004-09-29 | 2006-11-02 | Marc Mercken | Anti-amyloid antibodies, compositions, methods and uses |
CN101031300A (zh) | 2004-10-01 | 2007-09-05 | 默克公司 | 用于治疗或预防糖尿病的作为二肽基肽酶-ⅳ抑制剂的氨基哌啶化合物 |
WO2006042103A2 (fr) | 2004-10-05 | 2006-04-20 | Axys Pharmaceuticals, Inc. | Inhibiteurs reversibles de la cathepsine b |
BRPI0516446A (pt) | 2004-10-08 | 2008-09-02 | Novartis Ag | combinação de compostos orgánicos |
US9186345B2 (en) | 2004-10-12 | 2015-11-17 | Hakon Hakonarson | Method of treating skin diseases |
WO2006044497A2 (fr) | 2004-10-13 | 2006-04-27 | Merck & Co., Inc. | Composes de spiropiperidine utilises comme inhibiteurs de beta-secretase en vue du traitement de la maladie d'alzheimer |
EP1816996A4 (fr) | 2004-10-15 | 2009-08-12 | Biopharmacopae Design Internat | Methodes et compositions therapeutiques comprenant des extraits de plantes pour le traitement du cancer |
EP1812062B1 (fr) | 2004-10-25 | 2022-03-09 | Merck Sharp & Dohme Corp. | Anticorps anti-addl et leurs utilisations |
EP1807066A1 (fr) | 2004-10-25 | 2007-07-18 | Novartis AG | Combinaison d'inhibiteur de la dpp-iv, d'antidiabetique ppar et de metformine |
CN101048662A (zh) | 2004-10-28 | 2007-10-03 | 三光纯药株式会社 | 阿尔茨海默氏病的检验方法及诊断试剂 |
CN101052618A (zh) | 2004-10-29 | 2007-10-10 | 默克公司 | 用作治疗阿尔茨海默氏病的β-分泌酶抑制剂的2-氨基吡啶化合物 |
US7678783B2 (en) | 2004-11-17 | 2010-03-16 | Merck Sharp & Dohme Corp. | Macrocyclic tertiary amine beta-secretase inhibitors for the treatment of alzheimer's disease |
DE05852057T1 (de) | 2004-11-23 | 2007-11-29 | Neuromolecular Pharmaceuticals Inc., Emeryville | Zusammensetzung aus einer beschichtung oder matrix mit verzögerter freisetzung und einem nmda-rezeptorantagonisten sowie verfahren zur verabreichung eines solchen nmda-rezeptorantagonisten an ein subjekt |
AU2005309760A1 (en) | 2004-11-23 | 2006-06-01 | Merck & Co., Inc. | 2,3,4,6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease |
ATE512147T1 (de) | 2004-11-23 | 2011-06-15 | Merck Sharp & Dohme | Makrozyklische aminiopyridyl-beta-sekretase- hemmer zur behandlung von morbus alzheimer |
US8389578B2 (en) | 2004-11-24 | 2013-03-05 | Adamas Pharmaceuticals, Inc | Composition and method for treating neurological disease |
EP1819674B1 (fr) | 2004-11-29 | 2011-10-05 | Merck Sharp & Dohme Corp. | Aminopiperidines fusionnees utilisees comme inhibiteurs de la dipeptidyle peptidase-iv permettant de traiter ou de prevenir le diabete |
NZ554943A (en) | 2004-11-30 | 2010-12-24 | Hoffmann La Roche | Substituted benzoquinolizines as DPP-IV inhibitors for the treatment of diabetes |
WO2006060473A2 (fr) | 2004-12-03 | 2006-06-08 | Mucosal Therapeutics Llc | Methodes de traitement d'articulations lesees ou malades |
CA2589017A1 (fr) | 2004-12-15 | 2006-06-22 | Neuralab Limited | Anticorps amyloide beta utilises afin d'ameliorer la cognition |
WO2006066233A1 (fr) | 2004-12-15 | 2006-06-22 | Neuralab Limited | Essai d'immunoprecipitation permettant de predire l'efficacite in vivo d'anticorps anti-proteine beta-amyloide |
AR051528A1 (es) | 2004-12-15 | 2007-01-17 | Neuralab Ltd | Anticuerpos humanizados que reconocen el peptido beta amiloideo |
US8916165B2 (en) | 2004-12-15 | 2014-12-23 | Janssen Alzheimer Immunotherapy | Humanized Aβ antibodies for use in improving cognition |
WO2006066747A1 (fr) | 2004-12-20 | 2006-06-29 | F. Hoffmann-La Roche Ag | Derives de 4-aminopiperidine |
US7411093B2 (en) | 2004-12-20 | 2008-08-12 | Hoffman-La Roche Inc. | Aminocycloalkanes as DPP-IV inhibitors |
EP1828192B1 (fr) | 2004-12-21 | 2014-12-03 | Takeda Pharmaceutical Company Limited | Inhibiteurs de dipeptidyle peptidase |
JP2008525439A (ja) | 2004-12-23 | 2008-07-17 | ボイジャー・ファーマシューティカル・コーポレーション | アルツハイマー病の治療のための酢酸ロイプロリド及びアセチルコリンエステラーゼインヒビターまたはnmdaレセプターアゴニスト |
EP1831172B1 (fr) | 2004-12-28 | 2009-02-18 | Council of Scientific and Industrial Research | Esters d'acide carbamique quinoline-6-yle substitues utiles en tant qu'inhibiteurs de l'acetylcholinesterase |
US20080194548A1 (en) | 2005-01-06 | 2008-08-14 | Forrest Michael J | Drug Combination Therapy and Pharmaceutical Compositions for Treating Inflammatory Disorders |
CN101106994A (zh) | 2005-01-19 | 2008-01-16 | 默克公司 | 用于治疗阿尔茨海默氏病的氨基甲基β-分泌酶抑制剂 |
US7906625B2 (en) | 2005-01-24 | 2011-03-15 | Amgen Inc. | Humanized anti-amyloid antibody |
US20060216331A1 (en) | 2005-02-28 | 2006-09-28 | Lines Thomas C | Composition for treating mental health disorders |
WO2006094674A1 (fr) | 2005-03-07 | 2006-09-14 | Michael Hermanussen | Antagonistes de recepteur nmda dans l'intervention medicale de troubles metaboliques |
ES2259270B1 (es) | 2005-03-09 | 2007-11-01 | Consejo Superior De Investigaciones Cientificas | Metodo de diagnostico in vitro de la enfermedad de alzheimer mediante un anticuerpo monoclonal. |
WO2006099352A1 (fr) | 2005-03-10 | 2006-09-21 | Bristol-Myers Squibb Company | Nouveaux isophtalates utilises comme inhibiteurs de la beta-secretase |
FR2883285B1 (fr) | 2005-03-17 | 2007-05-18 | Sanofi Aventis Sa | Sel besylate de la 7-(2-(4-(3-trifluoromethyl-phenyl) -1,2,3,6-tetrahudro-pyrid-1-yl)ethyl) isoquinoleine, sa preparation et son utilisation en therapeutique |
ES2318918B1 (es) | 2005-04-01 | 2010-02-16 | Biotherapix Molecular Medicines, S.L.U. | Anticuerpos humanos con capacidad de union al peptido beta-amiloide y sus aplicaciones. |
EP1877045A2 (fr) | 2005-04-27 | 2008-01-16 | Novartis AG | Methodes de traitement de l'atherosclerose |
PE20061323A1 (es) | 2005-04-29 | 2007-02-09 | Rinat Neuroscience Corp | Anticuerpos dirigidos contra el peptido amiloide beta y metodos que utilizan los mismos |
TWI449692B (zh) * | 2005-05-13 | 2014-08-21 | Otsuka Pharma Co Ltd | 吡咯烷化合物(三) |
PE20061444A1 (es) | 2005-05-19 | 2007-01-15 | Centocor Inc | Anticuerpo anti-mcp-1, composiciones, metodos y usos |
WO2006137354A1 (fr) | 2005-06-21 | 2006-12-28 | Medical & Biological Laboratories Co., Ltd. | Anticorps avec effet inhibiteur sur la formation de fibrilles amyloïdes |
KR20150098683A (ko) | 2005-12-12 | 2015-08-28 | 에이씨 이뮨 에스.에이. | 치료적 특성을 갖는 베타 1-42 특이적인 단일클론성 항체 |
NZ568384A (en) | 2005-12-12 | 2011-09-30 | Ac Immune Sa | Therapeutic vaccine comprising Abeta peptide |
GB0704100D0 (en) | 2006-03-17 | 2007-04-11 | Vodafone Plc | Improvements in an ehspa architecture |
SG173385A1 (en) | 2006-07-14 | 2011-08-29 | Ac Immune S A Ch | Humanized antibody against amyloid beta |
DK2091945T3 (da) | 2006-11-09 | 2014-04-22 | Probiodrug Ag | Nye inhibitorer af glutaminylcyclase |
JP5379692B2 (ja) | 2006-11-09 | 2013-12-25 | プロビオドルグ エージー | 潰瘍、癌及び他の疾患の治療のためのグルタミニルシクラーゼの阻害薬としての3−ヒドロキシ−1,5−ジヒドロ−ピロール−2−オン誘導体 |
JP5523107B2 (ja) | 2006-11-30 | 2014-06-18 | プロビオドルグ エージー | グルタミニルシクラーゼの新規阻害剤 |
-
2011
- 2011-04-21 WO PCT/EP2011/056396 patent/WO2011131748A2/fr active Application Filing
- 2011-04-21 US US13/091,276 patent/US8541596B2/en active Active
- 2011-04-21 EP EP11715924.4A patent/EP2560953B1/fr active Active
- 2011-04-21 JP JP2013505486A patent/JP5945532B2/ja active Active
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6224244A (ja) | 1985-07-24 | 1987-02-02 | Konishiroku Photo Ind Co Ltd | ハロゲン化銀写真感光材料 |
JPS6255644A (ja) * | 1985-09-04 | 1987-03-11 | Konishiroku Photo Ind Co Ltd | ハロゲン化銀写真感光材料 |
US5106862A (en) * | 1986-10-27 | 1992-04-21 | Aktiebolaget Hassle | Derivatives of benzimidazoles active as anti-ulcer agents |
JPS63250385A (ja) | 1987-04-04 | 1988-10-18 | Tokuyama Soda Co Ltd | ハロゲン化複素環式化合物の製造方法 |
WO2000042022A1 (fr) | 1999-01-13 | 2000-07-20 | Warner-Lambert Company | Les benzoheterocycles et leur utilisation comme inhibiteurs de mek |
WO2001005770A1 (fr) | 1999-07-21 | 2001-01-25 | Fujisawa Pharmaceutical Co., Ltd. | Derives de benzimidazolone et leur utilisation comme inhibiteurs de la phosphodiesterase |
US6582351B1 (en) * | 1999-07-21 | 2003-06-24 | Fujisawa Pharmaceutical Co., Ltd. | Imidazopyridinone derivatives and their use as phosphodiesterase inhibitors |
WO2003077914A1 (fr) | 2002-03-13 | 2003-09-25 | Array Biopharma, Inc | Utilisation de derives de benzimidazole alkyles n3 en tant qu'inhibiteurs de mek |
WO2007053131A2 (fr) | 2004-06-04 | 2007-05-10 | Affinium Pharmaceuticals, Inc. | Agents thérapeutiques et méthodes pour les fabriquer et les utiliser |
WO2007002092A1 (fr) * | 2005-06-23 | 2007-01-04 | Array Biopharma Inc. | Procede snar de preparation de composes de benzimidazole |
WO2008055950A1 (fr) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | Nouveaux inhibiteurs de la glutaminyl-cyclase |
WO2008128985A1 (fr) | 2007-04-18 | 2008-10-30 | Probiodrug Ag | Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase |
Non-Patent Citations (12)
Title |
---|
Abuzar et al., Synthesis of N-Aryl- & N-Heteroaryl-benzimidazoles as Potential Anthelmintics, Indian Journal of Chemistry, 1980, pp. 599-600, vol. 19B. |
Brauniger et al., Darstellung von Desazaanalogen des Kinetins, Archiv der Pharmazie, 1966, pp. 13 and 194-196, vol. 299. No. 3, in German. |
Chemical Abstracts Service Registration No. (CAS RN) 1069857-25-5, entered Nov. 2, 2008, 1 page. |
Chemical Abstracts Service Registration No. (CAS RN) 1137428-36-4, entered Apr. 21, 2009, 1 page. |
Gallagher et al., Synthesis and photolysis of azido-benzo[b]thiophens, -benzothiazoles, -benzimidazoles, and -indazoles: Novel 6,7-Diamino-benzothiazoles, -benzimidazoles, and -indazoles and 6-Diethylamino-8H-thiazolo-[5,4-c] azepines, J Chem Soc Perkin I, 1980, pp. 2362-2370. |
JP62-024244 published Feb. 2, 1987, English abstract, downloaded from PAJ, 1 page. |
JP63-250385 published Oct. 18, 1988, English abstract, downloaded from PAJ, 1 page. |
Molnar, In 4,5-Stellung ungleich substituierte o-Nitraniline, Helvectica Chemica Acta, 1963, pp. 1779-1783, vol. 63, in German. |
Roy et al., Syntheses of 4,6-Dinitro-5-substituted-amino-benzimidazoles & 4,6-Dinitro-2-methyl-5-substituted-aminobenzimidazoles, Indian J Chem, 1979, pp. 164-166, vol. 17B. |
Soskic et al., Sythesis of N-n-Propyl-N-(2-arylethyl)-5-(1H-benzimidazol-2-thione)-ethylamines and Related Compounds as Potential Dopaminergic Ligands, Arzneim.-Forsch./Drug Res., 1996, pp. 741-746, vol. 46. |
Souillac, et al., Characterization of Delivery Systems, Differential Scanning Calorimetry in Encyclopedia of Controlled Drug Delivery, 1999, John Wiley & Sons, pp. 212-227. * |
Vippagunta et al., Advanced Drug Delivery Reviews, 48 (2001), pp. 3-26. * |
Also Published As
Publication number | Publication date |
---|---|
EP2560953A2 (fr) | 2013-02-27 |
EP2560953B1 (fr) | 2016-01-06 |
JP5945532B2 (ja) | 2016-07-05 |
WO2011131748A3 (fr) | 2012-03-15 |
JP2013525334A (ja) | 2013-06-20 |
US20110262388A1 (en) | 2011-10-27 |
WO2011131748A2 (fr) | 2011-10-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7803810B2 (en) | Inhibitors | |
US8772508B2 (en) | Inhibitors of glutaminyl cyclase | |
US8420828B2 (en) | Inhibitors | |
US9650362B2 (en) | Inhibitors | |
US9656991B2 (en) | Inhibitors of glutaminyl cyclase | |
US8962860B2 (en) | Inhibitors of glutaminyl cyclase | |
US8227498B2 (en) | Inhibitors of glutaminyl cyclase | |
US8202897B2 (en) | Inhibitors of glutaminyl cyclases | |
US9512082B2 (en) | Inhibitors of glutaminyl cyclase | |
US9181233B2 (en) | Inhibitors of glutaminyl cyclase | |
US8530670B2 (en) | Inhibitors | |
US8541596B2 (en) | Inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: PROBIODRUG AG, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HEISER, ULRICH;RAMSBECK, DANIEL;HOFFMANN, TORSTEN;AND OTHERS;SIGNING DATES FROM 20110511 TO 20110517;REEL/FRAME:026354/0907 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2552); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY Year of fee payment: 8 |
|
AS | Assignment |
Owner name: VIVORYON THERAPEUTICS N.V., GERMANY Free format text: CHANGE OF NAME;ASSIGNOR:VIVORYON THERAPEUTICS AG;REEL/FRAME:058250/0641 Effective date: 20210531 Owner name: VIVORYON THERAPEUTICS AG, GERMANY Free format text: CHANGE OF NAME;ASSIGNOR:PROBIODRUG AG;REEL/FRAME:057928/0117 Effective date: 20210531 |